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EXECUTIVE SUMMARY
Abstract: A "select universe" of 65,725 substances that are
of possible concern to the National Toxicology Program (NrIP)
because of their potential-for human exposure was
identified. Through a random sampling process, 675
substances covering seven major intenued-use categories were
selected. From this sample, a subsample of 100 substances
was selected by screening for the presence of at least some
toxicity information. In-uepth examination of this subsamp~e
led to the conclusion that enough toxicity and exposure
information is available for a complete health-hazard
assessment to be conducted on only a small fraction of the
subsample. On the great majority of the substances, data
considered to be essential for conducting a health-hazard
assessment are lacking. By inference, similar conclusions
were made for the select universe from which the sample and
the subsample were drawn. This report presents criteria for
selecting substances and determining toxicity-testing needs,
provides estimates of those needs, and describes some useful
criteria for assigning priorities for toxicity testing.
The potential public-health impacts of chemicals lead society to seek
information for determining the probability and magnitude of such
impacts. Such information is based primarily on predictions from results
of toxicity studies. The development of a strategy for obtaining
appropriate information requires an estimation of the quantity and
quality of available toxicity data applicable to the assessment of human
health hazard, as well as knowledge of the number of substances on which
necessary experimental data are not yet available. A characterization of
the magnitude of needed testing would be valuable to those who allocate
resources for such testing. However, because resources for Developing
sound scientific bases for identifying public-health hazards are limited,
it is important to establish priorities among chemicals and to select
those known or expected to have the greatest impact on human health.
A major function of the National Toxicology Program (NTP) is the
selection and testing of chemicals for toxicity. NTP has under
continuing review candidate chemicals for testing, as they are nominated
by the federal agencies served by the program, by state and local
governments, and by academic, industrial, and labor groups. Such
candidates are of interest to NTP because of their potential for human
exposure and public-health impact.
In September 1980, NTP, through the National Institute of
Environmental Health Sciences, contracted with the National Research
Council (NRC) and the National Academy of Sciences for a study. This
study was undertaken because NTP recognizes that the number of
substances, both natural and man-made, in the human environment is very
large and is increasing, with no clear indication of the nature and
amount of toxicity information that might be needed on these substances
1
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to ascertain their potential for adverse effects on human health. It is
useful for NTP to know as precisely as practicable the toxicity-testing
needs for substances to which humans are potentially exposed.
NTP asked NRC to address these matters in two major objectives of the
study:
(1) To characterize the toxicity-testing needs for substances to
which there Is known or anticipated human exposure, so that federal
agencies responsible for the protection of public health will have the
appropriate information needed to anticipate the extent of testing needs.
(2) To develop and validate uniformly applicable and wide-ranging
criteria by which to set priorities for research on substances with
potentially adverse public-health impact.
The study, titled "Identification of Toxic ana Potentially Toxic
Chemicals for Consideration by the National Toxicology Program, " was
established in the Board on Toxicology and Environmental Health Hazards
of the NRC Commission on Life Sciences.
In this report, the Committee on Sampling Strategies and the
Committee on Toxicity Data Elements describe in detail the criteria and
procedures they used to determine the nature and extent of toxicity
testing and their collective judgment on the testing needs for a "select
universe" of chemical substances. The underlying strategy for the
characterization of toxicity-testing needs involved four major steps:
(1) Definition of the select universe of substances that might be of
interest to NTP because of their potential for human exposure.
(2) Drawing of a random sample of representative substances from the
select universe.
(3) Statistical analysis of the sample to determine the quantity and
quality of available information and detailed description of testing
needs for the sample.
(4) Predictions, based on the sample analysis, of the testing needs
for the select universe.
The Committee on Priority Mechanisms presents criteria and a
decision-making framework that could be usea to set priorities for
research on substances with a potential for adverse public-health impact.
2
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SELECT UNIVERSE OF SUBSTANCES
According to an estimate based on the Chemical Abstracts Service (CAS)
Registry, the universe of known chemicals consists of over 5 million
entities. To define toxicity-testing neeas for substances in the human
environment, it was necessary to select a manageable subset of the
universe that would include most of the substances to which humans are
likely to be exposed in the United States. The construction of this
"select universe" of substances--a core that would be the reference for
the study--relied on a search for lists of substances preselected for
human exposure potential and computerized for reasonably easy access. A
search for such lists revealed several that could be assembled to form the
select universe, provided that most duplications of substances on the
combined lists could be identified to permit statistical adjustments. The
lists used included the Toxic Substances Control Act (TSCA) Inventory of
48,523 chemical substances in commerce; a list of 3,350 pesticides (active
and ine rt ingredients) registered for use by the Environmental Protection
Agency (EPA); a list of 1,815 prescription and nonprescription drugs
approved by the Food and Drug Administration (FDA) and excipients used in
drug formulations; a list of 8,627 food additives, including those
approved for use by FDA; and a list of 3, 410 cosmetic ingredients from the
Cosmetic, Toiletry and Fragrance Association. This select universe did
not systematically include environmental decomposition products,
manufacturing contaminants, or natural substances (e.g., plant pollens and
foods). The sum of the above, 65,725 entries from the lists, was taken as
the select universe for the purposes of this study. Statistical
adjustment for duplications indicated that the select universe contained
about 53,500 distinct entities. The Committee on Toxicity Data Elements
and the Committee on Sampling Strategies regarded the contents of the
select universe as closely approximating the expected universe of interest
to NTP.
CHARACTERI ~ I NG TOX IC I TV-TEST In NEEDS
During the planning stages of the study, it was recognized that the
Committee on Toxicity Data Elements would not be able to examine the
information on all 53,500 substances in the select universe, because of
limitations of available resources. Therefore, the Committee on Sampling
Strategies developed a method for drawing from the select universe a
sample that was (1) small enough to be thoroughly examined for
completeness, quality, and utility of information within the limitations
of available resources and (2) designed to permit an extension of the
committees' findings from the sample back to the select universe from
which it was drawn. With a stratified random process, 675 substances were
selected from the 65,725 listings. A random subsample of 100 substances
with at least minimal toxicity information (described in Chapter 2 of Part
1) as prescribed by the Committee on Toxicity Data Elements was then
selected from the random sample. The select universe, the sample, and the
subsample contained representatives of seven categories of substances
3
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defined by the lists that make up the select universe: (1) pesticides and
inert ingredients of pesticide formulations, (2) cosmetic ingredients, (3)
drugs and excipients in drug formulations, (4) food additives, and
chemicals in commerce, which were divined into (5) those with 1977
production of 1 million pounds or more, (6) those with 1977 production of
less than 1 million pounds, and (7) those whose 1977 production was
unknown or inaccessible because of manufacturers' claims of
confidentiality. The sizes of each category in the select universe, the
sample, and the subsample are presented in Figure 1.
The lists of substances making up the select universe were compiled on
the basis of intended use, rather than toxicity. The intended-use theme
was preserved throughout sample selection, data analysis, and
inference-making, and it is reflected in the conclusions. Some structural
classes of chemicals might be "overrepresented" in the subsample (e.g.,
cottonseed oil, linseed oil, and peanut oil). However, the Committee on
Toxicity Data Elements made no attempt to define the select universe by
chemical-structure classes. Rather, it relied on the probabilities
inherent in small random samples to choose an appropriate number of
substances from each major chemical grouping.
It is important to recognize that the subsample of 100 is drawn from
the seven categories defined above and that these categories often include
"inert" substances that are used to formulate "active" substances.
Furthermore, these categories are not defined by chemical structure, so
structurally similar substances in the subsample of 100 should not be
combined for inference to the select universe. Similarly, inferences
about a category should not be limited to the "active" substances in the
category (e.g., drugs), but rather should be applied to all the substances
(e.g., drugs and excipients in drug formulations) in that category. Nor
is the subsample representative of substances involved in specially
publicized episodes of toxic effect, such as those associated with
thalidomide or dioxins. These kinds of substances are often selected for
toxicity testing, because there is a particular interest in them--e.g.,
because some toxic effect has been observed. 'Thus, selection of
substances that have already had some testing aoes not necessarily
constitute random sampling of al1 possible substances in the select
universe .
The Committee on Toxicity Data Elements developed a well-structured,
stepwise approach to the determination of toxicity-testing needs for
substances in the select universe. This required agreement on a strategy
for judging the adequacy of toxicity data, establishment of guidelines for
assessing the quality of individual toxicity studies, and creation of a
decision-making system for reviewing and evaluating the total data base on
the hazard of a substance--its toxicity, its exposure potential for
humans, and its chemical and physical characteristics.
4
OCR for page 5
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Results of these efforts were applied to the subsample to establish
the extent of additional toxicity testing that might be needed. Data on
the sample and the subsample were then used by both committees to
estimate toxicity-testing needs for the entire select universe.
The Committee on Toxicity Data Elements judged the quality and
completeness of the toxicity data base on each substance in the
subsample. To ensure quality, available information was checked against
established reference guidelines for toxicity-testing protocols (e.g.,
those of the Organisation for Economic Co-operation ana Development) that
have been widely reviewed and generally accepted. The committee also
relied on the accumulated experience and expertise of its members, whose
combined judgment was used to determine the adequacy of an individual
study if it did not meet the standards of the reference protocol
guidelines. m e committee's determination of the adequacy of toxicity
testing for conducting a health-hazard assessment was based on
information derived from experiments performed according to the reference
protocol guidelines and other information that met the committee's own
basic criteria for evaluating scientific methods (described in Chapter 4
of Part 1~. Using this combination, the committee assessed the adequacy
of the toxicity-testing protocols and the need for further toxicity tests
in detailed evaluations, tabulations, and analyses for all substances in
the subsample. m e committees recognize that regulatory agencies'
standards and requirements for testing may differ from those used in this
study.
As analysis of the data bases proceeded, the Committee on Toxicity
Data Elements established a working document with a standardized format,
content, and method of reporting for each of the 100 substances in the
subsample as the focal point for all document control efforts and all
evaluations of testing adequacy. The working document or dossier became
the unit of record for all committee decisions and actions.
The approach developed to collect data on each substance included
searches of open literature (primary sources) through automated, on-line
data retrieval files; secondary-source literature, such as reference
manuals and textbooks; government technical reports; files of U.S.
regulatory agencies; and files provided by some chemical manufacturers
and trade associations. The data obtained from searches of the primary
and secondary open literature constituted the bulk of the information in
the dossiers. Search strategies were carefully developed to ensure the
most efficient screening of the data bases selected.
The findings of the Committee on Sampling Strategies and the
Committee on Toxicity Data Elements are based on analyses of the sample
of 675 substances randomly chosen from the select universe and the
subsample of 100 randomly chosen from the sample that had at least what
the latter committee defined as prescribed minimal toxicity information.
Some specific analyses are derived solely from the sample or the
6
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subsample. Others are derived from combined information on both the
sample and the subsample. Confidence limits are given for the results of
analyses in Chapter 5 of Part 1. In some cases, the confidence limits
are wide.
The committees recognize that, despite extensive efforts to obtain
all information, they might not have had access to results of some
toxicity tests. Toxicity-testing information on the subsample of 100
substances was sought from industries and other interested parties via a
Federal Register notice and by direct contact with manufacturers and
importers of sampled chemicals in commerce, but some industrial
information probably remained unavailable to the committees. Similarly,
the committees were not able to examine toxicity, physical, and chemical
information on cosmetic ingredients, drugs, excipients in drug
formulations, and food additives that may be in the files of FDA, except
in the case of food additives listed as substances generally regarded as
safe (GRAS).
The documentation for decisions about the quality of tests that have
been conducted and about toxicity-testing needs lends particular strength
to this study. Scientists have varied opinions about protocol guidelines
for toxicity tests, about testing needs for specific uses of substances,
and about grounds for claims of adequacy or inadequacy of a particular
test as it was performed. Where such varied opinions are important, they
can become an integral part of the decision-making process to provide new
estimates of testing needs. In the context of this study, scientific
judgments used by the committees were recorded and subjected to peer
review in a flexible study framework that would accommodate changes in
estimates brought about by the presentation of new data.
QUANTITY AND NATURE OF TESTING
It was recognized from the beginning that the quantity and nature of
testing needs were such that they could never be fulfilled adequately
only by the use of specific testing regimens. Although tests of
substances will always be needed, a better understanding of the ''how" and
"why" of toxic injury itself at the subcellular, cellular, organ, and
whole-animal levels will be necessary in the future to fulfill the needs
in the most efficient and economical manner. The Committee on Toxicity
Data Elements used a battery of toxicity tests as the basic "measuring
stick" for quantitation of testing needs. At the same time, it rejected
the concept that every substance in the select universe required the
adequate performance of a complete battery of toxicity tests for a
human-health hazard assessment, even if that were practical. Thus, other
criteria, including data from human exposures, were also used for
judgments about testing adequacy. The Committee on Toxicity Data
Elements recognizes that meeting the testing needs will require the
establishment of priorities for the tests and the substances needing them.
?
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In the seven categories of the sample of 67S substances, testing for
acute ana subchronic effects was generally present more frequently than
testing for chronic, mutagenic, or reproductive and developmental effects
(see Table 7 in Chapter 5 of Part 1~. On the basis of an analysis of the
randomly selected sample of 675 substances, 75% of the drugs and
excipients in drug formulations in the select universe have at least some
information on acute toxicity and 62% have information on subahronic
testing. For pesticides and inert ingredients of pesticide formulations,
these values are 59% and 51%, respectively. Testing was absent most
frequently for substances on the TSCA list of chemicals in commerce,
particularly for chronic, reproductive, and developmental effects.
More specifically, substances in the subsample of 100 were most
frequently tested with acute oral rodent studies and acute parenteral
studies (see Table 8 in Chapter 5 of Part 1~. Except for drugs and
excipients in drug formulations, the next most commonly conducted test
was for genetic toxicity. Dermal and eye irritation studies had often
been done with substances in the three production categories of chemicals
in commerce.
QUALITY OF TEST ING
The Committee on Toxicity Data Elements tabulated the quality ratings
from evaluations of a total of 664 tests of the 100 substances in the
subsample, without regard for either intended-use category or type of
test conducted (see Appendix H of Part l). When judged against currently
accepted standards for toxicity testing, only 8% of the tests in the
subsample met the standards of the reference protocol guidelines and
another 19% of tests performed were judged to be adequate by the
committee's standards. The percentages are based on the one study of
highest quality when two or more studies of the same type were done.
The quality of design, execution, and reporting of toxicity studies
was not uniform among the various types of experiments. Some test types
(acute oral administration in rodents, acute dermal application, acute
eye irritation and corrosivity, guinea pig skin sensitization, and
subchronic dermal application for 90 days) were deemed not to require
repetition in most cases where they had been conducted.
Four acute tests of substances In the select universe were often of
acceptable quality: acute oral administration in rodents (831), acute
aermal application (878), acute aermal irritation and corrosivity (81~),
and acute eye irritation and corrosivity (76~. Fewer chronic test types
were of acceptable quality; these included multigeneration reproduction
in rodents (33~), carcinogenicity in rodents (528), chronic toxicity
(38~), and combined carcinogenicity and chronic toxicity in rodents
(50%~. Overall, more testing is needed for chronic toxicity than for
acute toxicity. These findings should be viewed in perspective: the
comparison is of simple acute tests with more complex chronic tests;
8
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far fewer chronic tests were performed than acute tests; and, although
the percentages themselves are high, they are derived, on the whole,
from small numbers of evaluated tests, particularly in the case of
chronic studies.
Evaluation of individual study protocols by the Committee on Toxicity
Data Elements was always accompanied by documentation of the reasons for
the particular ratings given to the studies. For the most part, these
reasons were statements of specific adequacies or inadequacies in a
testing protocol. They were collectively tabulated for analysis to
assess which deficiencies were most prevalent and what values should be
placed on the deficiencies when the overall value of a study was assessed.
Some of the more common deviations from reference protocol guidelines
that nevertheless resulted in a test's being rated as adequate included
the use of too few animals per dosage group, the use of too few or
improper doses, and the absence of observations (e.g., in clinical
chemistry or histopathology). In most cases, such tests were considered
to have been conducted adequately because more information would not be
expected to alter the conclusions, because existing data were sufficient
to evaluate toxicity or calculate an acceptable LD50, or because doses
were high enough to give positive results or exceed the limit test
prescribed in the guidelines. The Committee on Toxicity Data Elements
notes that reference protocols are Developed for general application
before it is known which of their results will be important. The
committee judged the quality of studies after they had been performed and
in the light of the results obtained.
Tests that were rated as inadequately conducted often lacked required
observations (e.g., test animal description, diet analysis, chemical
analysis, clinical chemistry, and histopathology), used too few doses, or
lacked sufficiently detailed end points, such as data tabulation and
statistical analysis of data. Occasionally, the committee recommended
that these studies not be repeated, either because toxicity was
sufficiently well established or because more information would be of
slight value.
TOX ICITY-TEST ING NEEDS
For pesticides and inert ingredients of pesticide formulations, the
Committee on Toxicity Data Elements considered 18 test types to be
necessary according to the standards it adopted. In this category, all
studies of acute oral administration in rodents were judged not to
require repetition. Some of the 17 remaining test types needed
repetition or were not done at all from 20% to 73% of the time. For
cosmetic ingredients, this ranged from 67% to 100~; for drugs and
excipients in drug formulations, from 25% to 60%; for food additives,
from 33% to 80%; and for chemicals in commerce, from 45% to 100~. This
information indicates that, for each category of intended use,
substantial testing or retesting remains to be performed for all
categories of substances if information gaps are to be
9
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filled. The major gaps in testing result from failure to do tests
required by the committee according to the standards it adopted, rather
than from conducting tests Improperly (see Tables 12-18 in Chapter 5 of
Part 1~. If the unknown amount of information that was not available to
the committee had been available, the "untested" category would be
somewhat smaller than reported here.
In general, chronic studies, inhalation studies, and more complex
studies with specific end points (e.g., neurotoxicity, genetic toxicity
and effects on the conceptus) are most frequently needed. These were
among the test types considered by the Committee on Toxicity Data
Elements to be necessary for conducting a health-hazard assessment
according to the standards it adopted. There are some differences in
gaps in toxicity information from one category of substances to another
To some extent, these may reflect the spectrum of individual tests that
the committee prescribed as necessary to meet its criteria for adequacy
of information in each category.
The three greatest testing needs for health-hazara assessment of
pesticides ana inert ingredients of pesticide formulations were in
teratology, neurobehavioral toxicity, and genetic toxicity (see Table 19
in Chapter 5 of Part 11. For cosmetic ingredients, testing was found to
be needed most for subchronic eye toxicity and subchronic neurotoxicity.
A large variety of test types were found to be needed for drugs and
excipients in drug formulations, for food additives, and for the three
production categories of chemicals in commerce.
HEALTH-HA;6ARD ASSESShENT
The Committee on Toxicity Data Elements and the Committee on Sampling
Strategies made judgments to describe their ability to make health-hazara
assessments of substances in each of the seven categories of the select
universe as complete, partial, or none. A complete health-hazara
assessment was defined as one that provided a full estimate of hazard
associated with the safe use of a substance. A partial health-hazard
assessment was defined as one that provided a limited characterization of
the hazard associated with the safe use of a substance. Therefore, a
partial health-hazard assessment had a broad range extending from very
limited (e.g., acute-toxicity evaluation by one route of administrations
to almost complete (e.g., full acute- and chronic-toxicity evaluation,
except for inadequate neurobehavioral-toxicity determinations. The
estimates of percentages for health-hazard assessment combine data
obtained from the sample of 675 substances used to measure the existence
of minimal toxicity information and the 100 with minimal toxicity
information that were examined for the quality of test protocols.
Results of this analysis indicate not only the percentage of substances
in each of the seven categories in which sufficient data of adequate
quality are available for a heath-hazard assessment when judged against
the current standards for protocols, but also the percentage that would
require additional testing if an assessment were to be performed.
10
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The overall status of toxicity information and of the ability to
conduct a health-hazard assessment for each use category is presented in
Figure 2. In general, proportionately more testing has been undertaken
on pesticides and inert ingredients of pesticide formulations and on
drugs and excipients in drug formulations than on other substances. In
these two categories, 36% and 39% of substances met the requirements for
minimal toxicity information, respectively. The Committee on Toxicity
Data Elements judged it possible to make at least a partial health-hazaru
assessment for 94% and 92% of the substances with minimal toxicity
information in each of these categories, respectively.
Cosmetic ingredients ana food additives have been somewhat less well
tested. Minimal toxicity information requirements were met by 26% and
20% of substances in these categories, respectively, and at least a
partial health-hazard assessment was judged possible for 62% ana 95% of
the substances with minimal toxicity information in these categories,
respectively.
In contrast, only about 20% of the substances in each of the three
categories of chemicals in commerce have minimal toxicity information.
In all three categories, at least a partial health-hazard assessment was
possible for about half the substances having minimal toxicity
information. Virtually all the substances in the three subsampie
categories of chemicals in commerce with minimal toxicity information
would require additional toxicity testing if a complete health-hazard
assessment were needed. The frequency and quality of testing of
chemicals in commerce were not related to production volume. Chemicals
in commerce produced in quantities of 1 million pounds or more in 1977
have not been tested more often or more adequately than those produced in
smaller quantities.
INTERPRETATION OF PHYSI COCHEMI CAL AND EXPOSURE DATA
The committees attempted to relate the quantity and quality of
toxicity testing of each substance in the subsample to breadth of known
exposure, expected trends in exposure, physicochemical properties and
chemical fate of the substance, strength of evidence of toxicity in
humans, and severity of reported chronic human toxicity. In audition,
the committees sought information on occupational and environmental
exposure and attempted to relate it to the extent of testing needs.
It became evident as the dossiers for the 100 substances in the
subsample were examined that characterization of the substances with
respect to each of these factors, when possible, was basea on scanty
information. Most of the available information was on the
physicochemical properties of the substances; the least was on exposure.
However, no comprehensive method of gathering the needed information
could be identified, and, in the end, the principal basis for
characterizing exposure was the knowledge and expertise of the committee
members. The immediate use of substances In the synthesis of new
substances may not result in a reduction of exposure intensity, but will
reduce the number of persons exposed.
11
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Category
Size of Estimated Mean Percent
Category in the Select Universe
Pesticides and Inert
Ingredients of Pesticide
Formulations
Cosmetic Ingredients
Drugs and Excipients
Used in Drug Formulations
Food Additives
3,350
3,410
1.815
8,627
Chemicals in Commerce: 1 2,860
At Least 1 Million
Pou nds/Year
Chemicals in Commerce: 13,91 1
Less than 1 M il I ion
Pou nds/Year
Chemicals in Commerce: 21 ,752
Production Unknown or
I naccessible
24
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2 14 10 18
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18 18 3 36
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1
78
76
1
82
Complete
Health
Hazard
Assessment
Possible
Partial
Health
Hazard
Assessment
Possible
Minimal
Toxicity
I nformation
Available
Some
Toxicity
I Information
Available
(But below Minimal)
No Toxicity
I nformation
Available
FIGURE 2 Ability to conduct health-hazard assessment of substances
in seven categories of select universe.
12
l
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It should be emphasized that the stuay was Resigned to
characterize the status of tox~city-testing needs for substances to
which there is known or anticipated exposure, without regara in the
selection process to the extent of that exposure. The 100 selected
substances contained, in each category, few of the substances known to
be produced in the greatest volumes. Hence, this Study may not
provide an accurate estimate of the status of toxicity information on
the principal substances to which humans are exposed.
The following observations emerge from the committees' analysis:
· Of the 100 substances in the subsample, 42 (those with at least
minimal toxicity information) were considered to involve widespread
exposure. An additional 14 were considered to have limited exposure
potential, which would be intensive for specific groups.
· Physiocochemical data on 20 of the 100 substances lea to a high
concern about potential adverse human health effects. For 32
additional substances, the concern was moderate.
· There was no relation between the amount of testing that had
been performed and the degree of concern about a substance based on
physicochemical information.
Among the seven categories, it is the chemicals in commerce that
have the smallest amount of information relevant to human exposure in
the workplace and in the general environment. This is of particular
concern, inasmuch as the primary motivation for testing chemicals in
commerce is their potential for environmental and occupational
exposure.
The committees suggest that a coordinated effort be made to
collect information needed to assess potential human exposure in the
workplace and in the general environment. Development of analytic
methods; systems for monitoring ambient air, water, soil, ana togas;
personal monitoring systems; and highly sensitive and selective
instrumentation for the evaluation of human exposure should be
integral parts of this effort.
APPROACHES TO PRIORITY-SETTI NG
Part 1 of this report shows that, of tens of thousands of
commercially important chemicals, only a few have been sub~ectea to
extensive toxicity testing and most have scarcely been tested at all.
Many other constituents of the human environment, including natural
chemicals and various contaminants, are also potential
OCR for page 14
candidates for testing. Although it can be convincingly argued that
many chemicals do not need to be tested, because of their low
potential for human exposure or for toxic activity, it is clear that
thousands or even tens of thousands of chemicals are legitimate
candidates for toxicity testing related to a variety of health effects.
Many government and private institutions have responsibilities for
toxicity testing, and the National Toxicology Program has a special
mission to develop testing methods and to fill in the gaps left by
other institutions. However, the resources available to NTP for
testing--whether expressed in terms of budget, staff, or facilities--
are limited. Hence it must decide which chemicals to test and which
tests to perform. The need for priority-setting is especially acute
for lifetime bioassays, which may cost up to a million dollars for a
single chemical. Priority should presumably be assigned to chemicals
and tests that are in some sense the most important. The Committee on
Priority Mechanisms interpreted its charge to include defining "most
important" and indicating how to identify the chemicals and tests that
satisfy the definition. That is, the committee concluded that
definition of the goal of the testing program was essential to
designing a priority-setting system and that the goal would largely
drive the logic of the design.
Testing priorities have traditionally been assigned on the basis
of expert judgment, which is now supplemented with a variety of
analytic, data-based techniques, such as scoring systems. The
committee believes that this basic pattern should continue, with
further improvement in techniques to allow expert judgment to be most
effective. The committee recognized that no priority system, scheme,
or procedure can be perfect, because the knowledge needed for unerring
selection of the most important chemicals and tests is the same as the
knowledge resulting from a complete and accurate testing program for
all chemicals, which would of course make priority-setting
unnecessary. The priority-setting system and the testing program form
a continuum whose overall objective is to yield information of maximal
value about the overall hazards of chemicals.
In examining traditional approaches, including expert judgment and
mechanical priority-setting systems, the committee found some common
themes that can be considered conventional wisdom and with which it
agrees:
· Long lists of candidate chemicals need to be reduced to short
lists through screening, which yields increasing amounts of
information on decreasing numbers of chemicals and possible tests.
· me two key elements for screening are estimated human exposure
and suspicion of toxic activity. (This priority-setting effort is
oriented to human health and not to effects in other species, except
insofar as they point toward human effects.)
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· Chemicals that have already been tested adequately for a given
effect are of low priority for further testing for that effect.
Although documentation on the goals of most systems is somewhat
vague, all systems seem to use the goal of reducing the uncertainty
about the hazards of the population of chemicals in the human
environment as rapidly as possible within the limits of available
resources. The key elements embodied in this goal are hazard
-
(determined by both exposure and toxicity) and reduction of
uncertainty. Testing is needed most where uncertainty is greatest;
there is no need to continue testing for hazards that are already well
known. The above objective not only seems to be the common
denominator of current procedures for priority-setting, but is
obviously a worthy goal, because it allows society the best chance to
make decisions about chemicals that will reduce their hazards or at
least to accept them with full knowledge of the magnitude of their
hazards.
Of course, there are other legitimate goals of the testing program
and therefore of priority-setting. On the one hand, general
improvement in the understanding of chemical toxicity is worthy in
itself; on the other, testing directed at chemicals of great public
concern to confirm or deny the concern, and thus reduce anxiety, is
worthy. These goals are best addressed by subjective exercise of
expert judgment and were not addressed further by the Committee on
Priority Mechanisms.
Given a goal for the priority-setting system, the committee needed
to decide whether improvements over current procedures for selecting
chemicals for testing were possible. It concluded that improvements
were possible--at least at the margin--by injecting additional
systematic information-gathering and -processing procedures. Many
current procedures skirt the issue of the goal of the testing program
and therefore are somewhat inconsistent in approaching the goal. In
particular, the concept of the value of information is an important
contribution to systematic priority-setting. In brief, this concept
asserts that the value of any information-gathering activity, such as
toxicity testing or searching for information on human exposure to
chemicals, lies in the value of the resulting information in guiding
decisions. The contribution of this concept is in making explicit
that the goal of the testing program should be embodied in the
priority-setting system.
In the realm of chemical hazards, the "cost" of not knowing the
degree of toxicity of a chemical (or the degree of human exposure to
it) lies in misclassifying its hazard--e.g., believing that it is
innocuous, when it is actually toxic. Maximizing the value of
information about chemical hazards--or, equivalently, minimizing the
cost of misclassification of them--is therefore essentially the same
as the goal emphasized earlier. Thus, incorporating the
va2ue-of-information concept explicitly in the priority-setting system
provides an advantage, even though current procedures often use it
implicitly, even if erratically.
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The committee identified a second category of potentially
important improvements. It includes provisions for validating some
key estimates produced by the priority-sett~ng system and thereby
allowing for a self-improvement cycle to modify the system
accordingly. Current systems are difficult to validate, because they
rarely yield estimates that are directly verifiable, but simply
indicate which chemicals to test for which effects. The committee
proposes to redefine the elements of the priority-sett~ng system to
allow them to be checked. For example, an ideal system would estimate
the percentage of chemicals that would yield positive results if
tested; as experience accumulated, it would be possible to modify the
system on the basis of the errors in the estimates. We note again
that a priority-setting system cannot be free of errors in selecting
chemicals for testing or in classifying them by degree of hazard when
the test results are in, but any good system should reduce the
frequency of errors as information accumulates and improvements become
possible.
With these broad kinds of improvement in mind, the Committee on
Priority Mechanisms decided to outline an illustrative system that
would incorporate the stated goal and general features, building on
the experience of previous priority-setting procedures, but trying to
make them more systematic, defensible, and robust. The committee
recognized that its own resources were inadequate to develop a fully
operational priority-setting system with all the desirable features,
but it hoped to provide NTP with sufficient guidance and examples to
enable it to improve its current selection system while adhering to
its institutional operating principles.
Several design principles became evident and were used by the
committee in developing an illustrative priority-setting system:
O Any rational system can be conceptually divided into stages,
with more information on fewer chemicals and fewer potential tests in
each succeeding stage. The committee describes how a four-stage
system might be designed. In this system, Stage 1 acts as a coarse
screen and depends almost totally on automated information sources;
Stage 2 begins the use of expert judgment; Stage 3 relies heavily on
traditional expert judgment with only minor changes; and Stage 4 is
the testing program itself.
o Both exposure and suspected toxicity considerations are useful
in every stage of priority-setting. Information on either would
necessarily be relatively crude (that is, there would be relatively
little information about degree of hazards at early stages, but would
be correspondingly less expensive to acquire.
0 Many indicators of exposure and toxicity are available--e.g.,
for exposure: production volume, use patterns, and persistence; for
toxicity: chemical structure and the results of an acute test.
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Whether or not to use a specific indicator at a particular stage of
priority-setting depends on its cost, its individual value in
characterizing exposure or toxicity, and its combined value with other
indicators in characterizing degree of chemical hazards.
· me performance of a system should be evaluated according to
its ability to characterize the hazards of groups of chemicals, not
only its ability to indicate test-no test decisions.
· To accomplish test objectives, a system must take into account
the frequency of occurrence of various properties (e.g.,
carcinogenicity) and of various indicator values (e.g., a positive
result of an acute test) in groups of chemicals.
· An ideal system would be capable not only of dealing with a
relatively small number of chemicals nominated to NTP by agencies--as
in current practice--but also of dealing with a much larger number of
chemicals in the total select universe of concern (53,500, as stated
in Part 1 of this report). This capability does not necessarily imply
that NTP should be the entity that operates the long-list part of the
system.
· Expert judgment is essential for operation of the system beyond
the earliest stage, where judgment enters into the design but not into
the operation. Simply put, not enough is known about chemical hazards
to specify a purely mechanical system, and humans need to integrate
diverse data into judgments about the degrees of exposure and
suspected toxicity. However, these judgments should be made at the
lowest level of aggregation needed, because humans have Difficulty in
integrating information and concepts that are far outside their normal
range of experience.
Beyond these broad principles, possible designs for a
priority-setting system are multiple, and the specific choices for
design--let alone operation--depend on expert judgments. The
Committee on Priority Mechanisms offers in this report a possible
design (admittedly sketchy and incapable of immediate implementation)
that illustrates the key departures from current practice that seem
warranted. The design may look unfamiliar, because of its description
in mathematical terms, but it attempts to capture how a rational
person or group would set priorities for testing if able to gather,
assimilate, and integrate all the relevant pieces of information in a
completely informed and objective manner.
me reasoning behind the committee's design is presented in
Chapter 2 and Appendix B of Part 2. This reasoning depends in part on
a "model" of the system that allowed its operation to be simulated--in
highly simplified form--under a variety of assumptions. The reasoning
and system simulation are complex and may well challenge the reader;
however, they allowed the committee to explore the overall performance
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of various possible system designs with the goal of reducing
uncertainties about chemical hazards--an evaluation that has not been
typical in the past.
The result of exercising the model is the simplified system
description given in Chapter 3 of Part 2, in which the operation of
the illustrative system is described from the viewpoint of an outside
observer--what happens, but not why. Thus, Chapter 3 presents the
illustrative system as a "black box," whereas Chapter 4 and Appendix B
of Part 2 describe the "wiring diagram" for the interior of the box.
The committee believes that a fully developed version of the
outlined system not only is a plausible extension of current practice,
but also would provide some improvements over existing priority
setting procedures toward the goal defined earlier. Obviously, it
might not provide improvements toward other goals, but it should not
impede them. Even at the margin, the improvements would probably
easily justify the costs of developing, implementing, and operating
the system. However, the implementation of these concepts in the
illustrative system or one of similar scope would require adjustments
in the established patterns of thinking about testing priorities.
Specifically, full application of the proposed analytic techniques
will require that each information-gathering procedure be described
quantitatively with respect to its ability to identify and to
characterize potentially toxic chemicals. This requirement is not
readily fulfilled in our present state of knowledge. Hence, efforts
toward further quantification of the performance characteristics of
toxicologic methods would be essential to full implementation of the
priority-setting approach proposed herein. For this reason the
approach can be pursued initially on a pilot scale, with further
implementation depending on the development and availability of the
necessary data. The committee believes that it should be possible to
institute changes in current procedures gradually without irreversibly
committing resources to the novel features of its suggestions.
18
Representative terms from entire chapter:
toxicity data
