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OCR for page 81
-
RESULTS
A select universe of 65,725 listings of chemical substances was
compiled from lists of pesticides and registered inert ingredients of
pesticide formulations, cosmetic ingredients, drugs and excipients in
drug formulations, food additives, and other chemicals in commerce as
listed in the Inventory of the Toxic Substances Control Act. A sample of
675 substances chosen by a stratified random process was selected from
the 65,725 entries. A random subsample of 100 substances with at least
prescribed minimal toxicity information (see Chapter 2) was then selected
from the random sample. The sample and subsample contained
representatives of seven categories of substances: (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 divided into substances with (5) 1977
production of at least 1 million pounds, (6) 1977 production of less than
1 million pounds, and (7) 1977 production unknown or inaccessible owing
to manufacturers' claims of confidentiality.
The findings presented in this chapter are based on analyses of the
sample of 675 substances randomly selected from the select universe,
including data on the subsample of 100 (selected from the random sample
of 675) by application of criteria regarding the presence of minimal
toxicity information. Some specific analyses were based solely on the
sample or the subsample. Others were baser on combined information on
both the sample and the subsample. In each instance, the origin of the
information is stated to aid the reader in understanding the nature and
implications of the data.
The Committee on Sampling Strategies and the Committee on Toxicity
Data Elements recognize that their estimates of testing need may be less
than the reference protocol guidelines call for, even though some tests
may have been done not at all or not in compliance with the guidelines.
Although additional testing is desirable, some circumstances make it
unnecessary to perform some or all tests because other available
information--including that from prior testing of a substance, its
history of intended use, and other anticipated exposures to it (such as
occupational and environmental)--may permit some judgment of health
hazard in the absence of full data.
The reference protocol guidelines can be expected to change with
time, as public and scientific perceptions of hazards change, as the
technologic ability to detect hazard improves, and as willingness to
accept particular hazards changes.
Substances on the list of one category were often on lists of other
categories. The overlap among the seven categories was determined for
81
OCR for page 82
substances in the sample. This information provided the basis for
estimating that the select universe contained about 53,500 distinct
substances, the lower and upper 90% confidence limits being 49,800 ana
57,900, respectively. However, all reported findings are for specific
categories of the select universe, rather than for the select universe as
a whole. When categories or parts of them were combined, appropriate
weighting factors were assigned to account for duplication among lists.
Inert ingredients of pesticide formulations and excipients of drug
formulations were included in the select universe, because the Committee
on Toxicity Data Elements desired to include to the fullest extent in the
select universe the substances that were of possible interest to NTP
because of their potential for human exposure. Of the 50 pesticides and
inert ingredients of pesticide formulations in the sample, 37 were on the
list of active pesticides, 11 were on the list of inert ingredients, and
2 were on both lists; of the 15 in the subsample, 12 were on the list of
active pesticides, 2 were on the list of inert ingredients, and 1 was on
both. Of the 50 drugs and excipients in drug formulations, 22 were on
the list of active drugs, 18 were on the list of excipients, and 10 were
on both; of the 32 active drugs, 23 were listed as prescription drugs, 3
as nonprescription drugs, and 3 as both; of the 28 excipients, 13 were
found in prescription formulations, 1 was found in nonprescription
formulations, and 7 were found in both. Of the 15 in the subsample, 7
were listed as active drugs, 4 as excipients, and 4 as both; of the 11
active drugs, 8 were listed as prescription drugs, 1 as a nonprescription
drug, and 1 as both; of the 8 excipients, 2 were found in prescription
formulations, none was found only in nonprescription formulations, and 3
were found in both.
These numbers are presented to give the ensuing descriptive analyses
a sense of proportion regarding active pesticides, drugs, and nonactive
components of their formulations. The committees did not conduct
separate analyses to distinguish the findings for active ana nonactive
substances, although the data may permit others to consider such separate
analyses for their own purposes.
QUANTITY AND NATURE OF TEST ING
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 to fulfill future 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 requirea the adequate
82
OCR for page 83
performance of a complete battery of toxicity tests to make possible 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.
SAMPLE OF 675 SUBSTANCES
Minimal toxicity information was defined as specific combinations of
five basic types of tests prescribed by the Committee on Toxicity Data
Elements: acute, subchronic, chronic, repro~uctive/developmental,
and mutagenicity. The tests most frequently encountered for each
category of substances in the sample of 675 during the search for
prescribed minimal toxicity information are presented in Table 7. The
data in these tables include the best estimates of the Committee on
Sampling Strategies and the Committee on Toxicity Data Elements with
upper and lower 90% confidence limits. In some cases, confidence limits
are wide because of the unavoidable restrictions on sample sizes in
specific segments of the select universe.
As indicated in Table 7, 25-82% of the select universe was estimated
to have no toxicity information, on the basis of what the committees were
able to discover from the published and unpublished literature available
to them. In each of the seven categories of the sample of 675 substances,
testing for acute, subahronic, and mutagenic effects was present more
frequently than testing for chronic or reproductive/developmental
effects. For the select universe of drugs and excipients in drug
formulations, about 75% were estimated to have information on acute
toxicity and about 62% were estimated to have information on subchronic
testing. For pesticides and inert ingredients of pesticide formulations,
these values were about 59% and 51%, respectively. Testing was absent
most frequently for chemicals in commerce, particularly for chronic and
reproductive/developmental effects. All frequencies, even though some
were higher than others, are based on a limited number of substances that
had minimal toxicity information.
The degree of testing, as determined by the search for prescribed
minimal toxicity information and as presented in Table 7, was based on a
search strategy that was designed to qualify substances for the subsample
of 100 by rapidly identifying information where it was most likely to be
found. The rationale for this approach and the search strategy used are
presented in Chapter 3. The search was conducted for each of the 675
substances in the sample and may be assumed to be efficient in identifying
all or most of the existing information. However, unlike the search
strategy for the subsample of 100, it was not exhaustive. As a result,
the estimates presented in Table 7 may be slight understatements of the
amount of minimal testing that has been conducted.
83
OCR for page 84
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OCR for page 85
SUBSAME'LE OF 10 0 SUBSTANCES
-
Table 8 lists the test types used in the detailed analysis of the
subsample according to the degree to which they were performed on the
substances in each intended-use category that had the prescribed minimal
toxicity information. Acute oral rodent studies and acute parenteral
studies had been done most frequently. Except for drugs and excipients
in drug formulations, the next most commonly conducted test was for
genetic toxicity. Toxicokinetic, dermal, and eye irritation studies were
done on some chemicals in commerce. Except for the three categories of
chemicals in commerce, the test types encountered next most frequently
included investigations of effects of subchronic oral administration for
14, 28, or 90 d in rodents and of chronic oral administration. These
were followed in frequency by tests of teratology, acute skin and eye
irritation, carcinogenicity in rodents, acute dermal effects, and acute
inhalation effects. Acute oral administration in nonrodents and
subahronic oral administration for 90 d in nonrodents were also performed
occasionally. For the three categories of chemicals in commerce, studies
investigating carcinogenicity and subchronic toxicity in rodents were
also performed. The locations of the 33 test types in Table 8 are based
on small random samples, and the percentages of testing for specific
types might change if new random samples were examined.
It is evident from the results presented in Tables 7 and 8 that the
amount of testing information available on any category of substances is
related to the regulatory history of that category. In general,
proportionately more testing has been undertaken on drugs and excipients
in drug formulations and on pesticides and inert ingredients of pesticide
formulations than on other substances. Among all categories, drugs and
excipients in drug formulations have the longest history of regulatory
interest. Of the substances examined in this category, about 39% were
found to meet the requirements adopted by the Committee on Toxicity Data
Elements for minimal toxicity information. In contrast, only about 20%
of the compounds in the three categories of chemicals in commerce were
found to meet the requirements for minimal toxicity information,
although these requirements were much less strict than those adopted for
drugs and excipients in drug formulations.
The committees recognize that some toxicity tests may not have been
known to them. Although toxicity-test 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, some industrial
information probably remained unavailable. Similarly, the committees
were not able to examine toxicity, physical, and chemical information on
cosmetic ingredients, drugs, excipients in drug formulations, and food
additives contained in the files of FDA, except for food additives listed
as generally regarded as safe (GRAS).
85
OCR for page 86
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OCR for page 91
QUALITY OF TESTING
The Committee on Toxicity Data Elements often found that studies not
conforming to present testing protocol guidelines nevertheless yielded
acceptable results. The committee established six classifications to
describe the quality of test protocols:
O G. the highest rating, for a test protocol performed according to
current reference protocol Guidelines adopted by the committee.
· A, an adequate rating for a protocol that did not strictly follow
current reference protocol guidelines, but was nevertheless deemed
adequate for conducting a health-hazard assessment.
· IN, an inadequate rating for a protocol that was neither conducted
according to guidelines nor adequate for conducting a health-hazard
assessment, but was judged not to need repetition. This was used largely
because other adequately conducted tests provided the necessary or
closely related information or because available information was deemed
to be sufficient for conducting a health-hazard assessment.
· IR, an inadequate rating for a protocol that was neither adequate
nor conducted according to guidelines and that was judged to need
repetition.
· C, a rating denoting indeterminable quality of a test that could
not be judged. This rating was most frequently given to abstracts,
review articles, and other reports that did not describe protocols fully.
· X, a notation for a test that, according to available information,
was not done.
Table 9 shows the quality ratings of the 33 test types as found to
have been done on the 100 substances in the subsample. The proportion of
substances on which a given test type was not run (X) ranged from 37%
(acute oral testing in rodents) to 100% (subchronic eye toxicity testing).
Overall, without regard for either test type or intended-use
category, the Committee on Toxicity Data Elements tabulated the quality
ratings from evaluations of a total of 664 tests. A tally of these
quality ratings for each subsample category and for the subsample as a
whole is presented in Table 10. Only about 8% of the tests met the
standards of the reference protocol guidelines, and about another 19%
were judged to be adequate. When more than one study of the same test
type had been done, these percentages are based on the quality rating of
the best study.
91
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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: 12,860
At Least 1 Million
Pounds/Year
Chemicals in Commerce: 13,91 1
Less than 1 Million
Pounds/Year
Chemicals in Commerce: 21,752
Production Unknown or
I naccessible
Complete
Health
Hazard
Assessment
Possible
10 24
2 26
38
_ ////1 1
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2 14
56
11 11
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25
46
78
76
82
//
Minimal
Toxicity
Partial
Health
Hazard
Assessment Available
Possible
Some
Toxicity
Information
Available
(But below Minimal)
No Toxicity
Information
Available
FIGURE 2 Ability to conduct health-hazard assessment of substances
in seven categories of select universe.
118
OCR for page 119
a substance. A partial health-hazard assessment is defined as one that
has a limited characterization of the hazard associated with the safe use
of a substance. Therefore, a partial health-hazard assessment has a
broad range extending from very limited (e.g., acute toxicity by one
route of administration) to almost complete (e.g., full acute-toxicity
and chronic-toxicity evaluation except for inadequate neurobehavioral-
toxicity determination).
The percentages of the select universe in Table 20 and Figure 4 are
estimates based on analysis of the subsample of 100 substances, all of
which met the prescribed requirements for minimal toxicity information.
Results of this analysis indicate not only the percentage of substances
in each of the seven categories that have sufficient testing of adequate
quality to conduct a health-hazard assessment, but also the percentage
that would require additional testing according to the standards adopted
by the Committee on Toxicity Data Elements if an assessment were to be
performed. It should be remembered that the requirement for minimal
toxicity information (see Chapter 2) varied among the seven categories.
Chemicals in commerce were considered to have met the requirement if any
one of the five tests used to define minimal toxicity information were
done. Therefore, chemicals in commerce that had less than minimal
toxicity information as determined by the search strategy used had, by
definition, no information.
In general, proportionately more testing has been undertaken on
pesticides and inert ingredients of pesticide formulations and on drugs
and excipients in drug formulations. 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-hazard assessment of 94% and 92%,
respectively, of the substances with minimal toxicity information.
Cosmetic ingredients and food additives have been somewhat less
thoroughly tested. Minimal-toxicity-information requirements were met by
about 26% and 20% of substances in these categories, respectively, and at
least a partial health-hazard assessment was judged possible for about
62% and 95%, respectively, of the substances with minimal toxicity
information.
In contrast, only about 20% of the substances in each of the three
production categories of chemicals in commerce had minimal toxicity
information; at least a partial health-hazard assessment was judged
possible for about 50% of the substances with minimal toxicity
information in each of the three categories. Virtually all the
substances in the three subsample categories of chemicals in commerce
with minimal toxicity information required additional toxicity testing if
a complete health-hazard assessment were to be performed. Chemicals in
commerce with indicated 1977 production of at least 1 million pounds have
been tested no more often or more adequately than substances with 1977
production of less than 1 million pounds.
119
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It is evident that, even in categories in which the greatest amount
of testing has been done, there is still a great deal to do. For the
chemicals in commerce, this arises in part from the facts that regulation
of these substances has come about only recently and that the regulatory
requirements for testing have generally been less than those for
substances in the other categories. The three categories of chemicals in
commerce also do not specifically reflect the substances of greatest
commercial use. Exposure information may be present to a greater degree
on such substances than on those selected for the sample.
INTERPRETATION AND ANALYSIS OF PHYSICOCHEMICAL AND EXPOSURE DATA
The committees attempted to relate the quantity and quality of
toxicity testing to several factors that seem to be logical determinants
of testing, such as breadth of known exposure, expected trends in
exposure, physicochemical properties and chemical fate of the substances,
and strength of evidence of toxicity in humans, including the severity of
reported chronic human toxicity. In audition, the committees sought
information on occupational and environmental exposure and attempted to
relate this information to the extent and quality of toxicity testing.
These efforts were limited to substances in the subsample.
As the dossiers for the 100 substances in the subsample were
examined, it became evident that characterization of the substances with
respect to each of these factors, if it was possible at all, was based on
sparse information. Most 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 information was the knowledge and expertise of
the committee members. For example, a judgment about widespread exposure
was made on the basis of available information--such as the number of
persons exposed in occupational or environmental settings, production
volumes, environmental stability, or number of drug prescriptions
sold--or on the individual experience and personal knowledge of committee
members. It is possible that exposure information is more complete on
substances of greatest commercial importance than on other substances.
Information on physicochemical properties and potential exposure was
tabulated and tallied as present or absent, but its quality and quantity
were not assessed. Therefore, conclusions drawn from these data should
be interpreted conservatively. A multiple-choice summary checklist (see
Appendix L) for each substance in the subsample of 100 was completed by
the Committee on Toxicity Data Elements after review of all information
in the dossier. These data were then examined for correlations among
amount and quality of testing, potential for exposure, knowledge of
physicochemical properties, and concern for potentially adverse human
health effects.
120
OCR for page 121
Because the samples were small and sampling in the several categories
of substances was not proportional, averages or percentages based on
totals could be misleading, especially for larger groupings of
substances, and particularly if they are taken to be firm estimates.
Furthermore, because the numbers are small, detailed inferences to the
select universe are not appropriate. Nonetheless, the findings will give
the reader a reasonable impression, based on the subsample of 100
substances, of how the data are arrayed.
The following observations are apparent from the committees' analysis:
· Of the 100 substances in the subsample, 42 were known to have
widespread exposure. An additional 14 had limited exposure potential,
which, however, would be intensive for specific groups.
~ For 20 of the 100 substances, physicochemical data led to a high
concern about potential adverse human health effects. For 32 substances,
there was moderate concern.
· The amount of testing that had been performed was not related to
the committee's judgment that the chemicals warranted additional concern
on the basis of physicochemical information.
Of the seven categories, more information was generally available on
the four that had specific, regulated uses than on the three categories
of chemicals in commerce. The committees believe that this might be the
result of two factors: In contrast with the other four categories,
chemicals in commerce have not been subject to regulation until recently
and thus toxicity testing has been required for a shorter time; and the
four categories that have been subject to regulation for a longer time
are also those to which humans are intentionally exposed and which would
therefore be of greater concern to toxicologists. The committee members
recognize that these reasons are interdependent.
Table 21 summarizes the extent of availability of various kinds of
data on substances on which a partial or complete health-hazard
assessment could be conducted. Within the seven categories, data on
solubility or partition coefficient, physical state, manufacturing
process, and melting or boiling point were least available for substances
in the three categories of chemicals in commerce.
Other chemical data that were available could assist in conducting a
health-hazard assessment. Chemical-reactivity data were most available
for the pesticides and inert ingredients of pesticide formulations (73%),
drugs and excipients in drug formulations (6711, food additives (47~),
the three production categories of chemicals in commerce (20-45%), ana
cosmetic ingredients (40%~. Chemical-reactivity data were considered to
be available if there was any information on hydrolysis, photochemical
changes, potential for absorption or Resorption, or nonbiologic systems,
including shelf-life and oxidation and reduction potential.
121
OCR for page 122
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Of all the types of chemical information sought, data on the overall
availability of analytic methods were least available (0-27~. Analytic
methods were considered to be available if there was any information on
the pure substance only in nonbiologic systems, on chemical reactions in
biologic systems, or on evaluation in environmental media (air, water,
and food) or direct human substrates (urine, blood, other body fluids,
and tissues). Data elements concerning use, production processes and
volumes, chemical bioavailability, and exposure related to the workplace,
the general environment, and intended use are necessary to assess the
relation between exposure potential and overall health hazard. Data on
intended-use exposure or, where appropriate, indications of uses other
than those intended (e.g., drug abuse) were more readily available for
pesticides and inert ingredients of pesticide formulations (67~), drugs
and excipients in drug formulations (100~), cosmetic ingredients (67%),
and food additives (608) than for chemicals in commerce (0-30~. Data
elements involving bioavailability were available for 73% of pesticides
and inert ingredient of pesticide formulations and for 20% of the
low-volume chemicals in comme rce . Information on bioavailability was
considered available if there was any information on environmental
stability and turnover rates; biodegradation; excretion and elimination;
occurrence in air, water, tissues, or food chains; or bioaccumulation.
Data related to occupational and environmental exposure potentials
frequently were absent, ranging from 45% to 100% absent in the seven
categories.
The availability of data concerning occupational or intended-use
exposure had little or no relation to whether the literature contained
information on bioavailability or environmental exposure. Pertinent data
concerning the determination of exposure were scanty, even though
exposure assessment is inherent in any approach to health-hazard
assessment.
Although the committees' standards for judging the presence of
various types of physicochemical charateristics were liberal, the
proportions of substances without such data are high. The hazards
associated with human exposure to chemicals depend on the nature,
frequency, and intensity of exposure, as well as on the toxicity of the
chemicals. The major activity of the committees, however, was devoted to
an analysis of the quality and quantity of the toxicity data base, and
the bulk of this report describes the analytic process and the results of
the analysis. Although the committees acknowledge the importance of both
exposure and toxicity data in hazard evaluation, they recognized that it
would not be possible to use an approach that assembles an exposure data
base amenable to the kinds of systematic analysis applied to the toxicity
data base. The following are among the many factors that limit the
application of such an approach:
· There are few legal reporting requirements for human exposure to
chemicals. Even data on production volumes of substances and numbers of
people involved in manufacture, distribution, use, and waste disposal are
limited.
123
OCR for page 124
· There is little incentive for voluntary reporting of either
production or exposure data in the open literature or in accessible
agency files, and the few data available are often reported in forms that
limit their comparability.
· Environmental-concentration data collected for compliance
monitoring--such as coal-mine dust content, ambient-air concentrations of
criteria pollutants, and concentrations of pesticide residues in
foods--are for specific substances that were not in the random sample
selected for this study. Furthermore, data collected for compliance
monitoring may be of limited value in evaluating population exposures.
~ Little is known about physical processes and procedures that
affect the exposure potential for uses other than those intended. For
example, the intensity of occupational exposure is strongly influenced by
the choice of process and control equipment, and the intensity of
environmental exposure is strongly influenced by the selection of
waste-disposal technique, chemical reactivity, and degree of
biodegradability.
In view of the great importance of exposure data and indexes of
hazard assessment and the nearly complete absence of such data, the
committees recommend that planning begin for the development of much more
'I than now exist for exposure
The committees recognize that this will require a
substantial effort and allocation of resources. It will also depend on
further interagency collaboration and communication.
extensive, detailed, and accurate data bases
assessments.
124
Representative terms from entire chapter:
select universe
