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OCR for page 301
APPENDIX A
REVIEW OF SELECTED PRIORITY-SETTING SYSTEMS
Initial examination of selected priority-setting schemes revealed
that the multiplicity of approaches was more apparent than real. The
appearance of dissimilarity arises more from differences in emphasis, or
scope, than from differences in basic logic or strategy.
Selected for detailed description here are schemes that were thought
to make important contributions to the developing science or art of
priority-setting. The choices in some cases were related to uniqueness
in the treatment of exposure, of toxicity, or of the interaction between
the two. A comprehensive list of schemes has been compiled (U.S.
Environmental Protection Agency, 1980~. It has been recommended that
federal agencies adopt priority-setting systems (Administrative
Conference of the United States, 1982~.
The Toxic Substances Control Act-Interagency Testing Committee
(TSCA-TTC) scheme (Nisbet, 1979) is of particular interest, because it
deals with a large part of the universe with which the NTP is concerned.
Equally important, it has had to face the test of continued use over
several years, and it has been systematically reviewed (Nisbet, 1979~.
The schemes of Kornreich et al. (1979 ) and Ross and Lu (1980) are
based on a systematic review of a substantial portion of the literature
on priority-setting. The Food and Drug Administration (FDA) scheme (U.S.
Department of Health and Human Services, 1982) is limited to one route of
exposure, but otherwise is comprehensive in its approach. The scheme of
Wilhelm (1981) is in large measure a response to what were perceived as
deficiencies in the TSCA-ITC system. That of Astill et al. (1981) is
designed to function with a sequential testing and feedback strategy.
The ranking algorithm of Brown et al. (1980) is based on a simple
mathematical model and is designed for multinational application. The
proposed cyclic review procedure for FDA (U.S. Department of Health and
Human Services, 1982) uses structure-activity considerations to establish
initial "levels of concern," which are also found in the decision-tree
approach of Cramer, Ford, and Hall (1978~. Gori's
scheme (1977) provides
a ranking index based on exposure that is complementary to a second
scheme that uses structure-activity analysis for assessing possible
carcinogenic activity (Dehn and Helmes, 1974~.
NATIONAL TOX ICOLOGY PROGRAM
The NTP chemical nomination and selection process, as described in
the NTP Fiscal 1983 Annual Plan (U.S. Department of Health and Human
Services, 1983), is summarized below.
301
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CHEMICAL NOMINATION
Member agencies of NTP and other sources (other federal agencies,
state agencies, the public, labor, and industry) submit to NTP
nominations of chemicals for various types of toxicity testing. Each
nomination is expected to include the name of the chemical, the
particular toxicity testis) desired, the rationale for the nomination,
and the available background data on production, use, exposure,
environmental occurrence, and extent of toxicologic characterization.
All nominations are considered, however, regardless of the depth of
information submitted.
Nominations are referred to the NTP chemical selection coordinator
for review, to determine which chemicals have been tested, are already on
test or scheduled for test, or have been previously considered and
rejected for testing by NPT or its predecessors. This may involve
preliminary searches of on-line data bases and reference books. The
nominations and background information are then forwarded to the
chemical-review staff at the National Center for Toxicological Research
(NCTR), who examine the available literature, assess the relevant data,
and prepare draft executive summaries of the information. (Executive
summaries are not prepared for chemicals nominated solely for
mutagenicity testing.) Included in each draft executive summary are
chemical identification, surveillance index (production, use, occurrence,
and analysis), information on toxic effects, and a statement of the
source of and reason for nomination.
EVALUATION OF NOMINATED CHEMICALS
The chemical-review staff sends the draft executive summaries to the
Chemical Evaluation Committee (CEC), which is composed of representatives
of the Consumer Product Safety Commission (CPSC), Environmental
Protection Agency (EPA), FDA, Occupational Safety and Health
Administration (OSHA), National Cancer Institute (NCI), National
Institute of Environmental Health Sciences (NIEHS), National Institute
for Occupational Safety and Health (NIOSH), NCTR, and NTP. Members are
requested to search data bases peculiar to their agencies for further
information on the nominated chemicals (and structurally related
compounds), to improve the evaluation process. The CEC evaluates the
summaries and recommends the types of testing to be performed. Primary
and secondary reviewers are also assigned to each chemical, after
consideration of the nature of exposure, so that appropriate regulatory
concerns will be addressed.
At the CEC meetings, the primary reviewer for each chemical
summarizes the data on that chemical and makes recommendations for
testing. The secondary reviewer presents additional information, where
available, and also discusses the testing of the compound. After
discussion, the CEC votes on the recommended types of testing and assigns
priorities for the testing.
302
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PUBLIC COMMENT
A Federal Register notice is published, which lists the chemicals
reviewed by the CEC and the recommended types of testing. The notice
also solicits comments from interested parties and information on
completed, current, and planned testing in the private sector. The list
of chemicals is also published in the NTP Technical Bulletin, with a
request for comments. These steps are taken to enable other individuals
and groups to provide data useful to the chemical evaluation process.
PEER REVIEW
The revised executive summaries and public comments on the nominated
chemicals are forwarded to the NTP Board of Scientific Counselors, which
meets to evaluate the data and to make recommendations.
CHEMICAL SELECTION
The chemical-review staff then incorporates the board's ratings and
pertinent public input into final executive summaries, which are
submitted to the NTP Executive Committee. That committee decides whether
to test, defer, or delete each of the nominated chemicals for the various
types of testing. Its decisions are published in the NTP Technical
Bulletin. The committee also recommends priorities for testing, test
development, and test validation to NTP.
After Executive Committee action, the NTP Steering Committee refers
the chemicals to one or more of the three organizational units
participating in NTP: NIEHS, NIOSH, and NCTR. A chemical manager is
then assigned to evaluate the data developed during the NTP chemical
evaluation process and other information retrieved from detailed searches
of the published literature and from industry. The manager presents a
proposal to the Toxicology Design Committee (TDC) either to perform
appropriate testing or to delete the chemical from consideration for
testing. The TDC, which consists of research scientists from NIEHS and
NTP, assesses the proposal and either develops a final protocol for
testing or recommends no further testing; the latter recommendation is
based on technical difficulties in testing, budgetary reasons, or the
existence of adequate outside testing.
All chemicals selected through this process are then tested as time
and resources permit.
The results of testing are reviewed routinely, to determine whether
further types of testing are appropriate, and candidates for additional
testing are submitted to the NTP chemical nomination and selection
process for evaluation and decision-making.
303
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SEQUENTIAL TESTING FOR CHEMICAL RISK ASSESSMENT
(ASTILL ET AL. t 1981)
This scoring system was developed by the Eastman Kodak Company to
~ the extent of toxicity testing required for production
Four categories of information are used to derive a total
the basis of which one of four testing levels is recommended.
determine
chemicals.
score, on
Available health and environmental data are compiled and rated
independently, composite health-effects scores are computed, and the
appropriate tests are selected and performed. Results of these tests are
then used to revise the ratings. New scores are obtained, and the
testing level is revised. This process is repeated until testing
information is complete. Thus, the system is dynamic, in that it
incorporates a feedback mechanism that allows for continuing review of
the testing needs of a specific chemical. This system provides a basis
for a multistage screening system.
Four categories of information are used: magnitude of human
exposure, magnitude of environmental exposure, effects on human health,
and effects on the environment. The two magnitude categories have four
components each, and the two effects categories have three components
each.
The four components considered in the rating of the magnitude of
human exposure are production volume, number of people exposed, hours per
year exposed, and number of population types exposed. Scores for the
four components are added to yield a value
for the magnitude of
exposure. The assessment of health effects considers the LDso, acute
effects (reversible and irreversible!, and chronic effects (reversible
and irreversible).
four categories is scored from 1
Each of the 14 components of the _ _ ~ _ ~
3, with 3 indicating the most severe or hazardous score. The scores
_ to
The scores for
the two human categories thealth effects and magnitude of human exposure)
are summed, as are the scores for the two environmental categories. The
resulting scores range from 7 to 21 and are associated with specific
testing levels, as follows:
Health (or Environmental) Score
7 - 9
10-13
~ 4 -17
18-21
-
Testing Level
II
III
IV
The level of testing becomes increasingly specific and sophisticated
with increasing score. Level I testing is based on the use of
physicochemical evaluation and health screening, as well as acute-toxicity
304
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studies. Although it is not specifically stated, with respect to human
data, Level I might include surveillance of morbidity, mortality, and
fertility patterns of exposed human populations. Level II testing consists
of toxicity tests that are intermediate between acute tests and subahronic
feeding studies, whereas Level III testing includes subacute exposure
studies. Long-term (or chronic) health effects are evaluated through Level
IV testing.
The health-effects criteria are not very specific, but readily
quantified in an objective and replicable manner. The health-effects
criteria and ratings are as follows:
LD50, mg/kg
Immediate effects
Prolonged effects
Rating
> 500 1
50-500 2
50 3
2
None
Reversible
Irreversible 3
None 1
Reversible 2
Irreversible 3
This system appears to be efficient, in that it uses a minimum of
subjective input (expert opinion or judgment), although such judgment may be
used in the review and rating of health effects.
This system appears to be practical, in that it facilitates
decision-making in an efficient and objective manner. Any compound can be
evaluated; in the absence of available data, baseline information is
compiled before any testing is done. The baseline information compiled
consists of:
Quantities manufactured and disposed of.
Exposure estimates.
Product function and application.
Structure-activity correlation.
.
· Literature search.
Cancer hazard evaluation.
Such baseline information may be sufficiently complete for hazard
assessment, particularly if previously published toxicity studies are
available.
305
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This scheme has been evaluated by the authors with a wide range of
industrial chemicals, although the specifics of evaluation are not provided.
A RANKING ALGORITHM FOR EEC WATER POllUTANTS
(BROWN ET AL., 1980)
The purpose of this scheme is to rank, for possible regulatory action,
water pollutants as potential hazards to humans and to aquatic organisms.
The scheme considers about 1,500 compounds used in countries of the European
Economic Community and suspected of entering rivers.
The algorithm is based on a simplified mathematical model relating
production and use of a chemical to its occurrence in drinking water and in
food of freshwater origin. Standard assumptions are made as to intake of
fish and water; daily maximal and annual average intakes through ingestion
are calculated.
The amount of a chemical estimated to reach the water is calculated by
multiplying production by the fraction that reaches the water; the fraction
is estimated on the basis of manufacturing practices and the chemical's
use. A typical dilution volume of the chemical is estimated from its
half-life in water and from river-flow data. Estimated concentrations are
used to calculate human exposure from consuming drinking water and
freshwater fish. A concentration factor is used to calculate ingestion from
consumption of f ish, assuming typical diets.
The list of 1, 500 chemicals was reduced to about 1,400 when mercury and
cadmium compounds were eliminated because they were already controlled by
the EEC and persistent synthetic substances (mainly plastic materials) were
eliminated because, although objectionable in water, they are not toxic.
For the remaining 1,400 compounds, production and consumption data are
obtained, and all those estimated to be produced at under 100 metric tons
per year are eliminated. The remaining 426 compounds are then processed
through a screening algorithm based on production, environmental half-life,
and acute-toxicity factors.
Some elements of toxicity testing for human health are applied in this
scheme. The acute-mammalian-effect dose is represented by the lowest
reported lethal oral dose for humans. If this information is not available,
the lowest oral LD50 value for other mammalian species is used. If no
oral LD50 value is available, the lowest LD50 value for the dermal or
inhalation route is applied. If no LD50 values have been reported at all,
the lowest lethal dose for the oral, dermal, or inhalation route is used.
If no acute-lethality data are available, an estimate is devised on the
basis of comparison with other compounds in the same chemical class. If a
reasonable estimate cannot be made this way, the default entry "unknown" is
used in the program.
306
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Chronic mammalian effects are also used when available. If the data
file indicates that carcinogenicity, mutagenicity, or teratogenicity
information is available, it is factored into the algorithm. If a chemical
exhibits all three effects, only one is entered, preferably
carcinogenicity. The chronic-mammalian-effect dose is the lowest dose that
caused the reported effect.
ESTIMATION OF TOXIC HAZARD--A DECISION TREE APPROACH
(CRAMER ET AL., 1978)
This scheme ranks food chemicals in three classes of concern for
toxicity testing on the basis of chemical structure and oral-toxicity data.
It is applied to structurally defined organic and organometallic compounds.
Polymers and inorganic compounds are excluded.
By answering a series of questions about chemical structure, the
operator of the system follows a decision tree until the chemical considered
falls into Class I (low concern), Class II (moderate concern), or Class III
(serious concern). In each class, chemicals are ranked by comparison witn
no-observed-effect doses. The data on no-effect doses were derived from
literature values based on short-term or chronic studies.
Class I substances are those whose structures and toxicity data, when
combined with low human exposure, suggest low priority for investigation.
Class III substances are those whose structures and toxicity data would not
permit presumptions of safety and which thus require the highest priority
for investigation. Class II substances are intermediate between Classes I
and III. High exposures to substances in any class would increase the
priority for investigation or testing. The number of chemicals found to be
in Class II is not large.
The tabulation of compounds in classes, with the exception of compounds
with no-effect exposures above 500 mg/kg of body weight per day, is
restricted to toxicity tests in which the next higher feeding exposure above
the no-effect exposure is no more than 5 times the no-effect exposure. It
was the general intent of the authors that the most toxic substances in
Class I (low concern) should have a no-effect exposure in animal tests at or
above SO mg/kg of body weight per day. This exposure, subjected to a safety
factor of 100, corresponds to human exposure at approximately 25 mg/day.
Use of this procedure requires knowledge of chemical structure and
reasonably accurate estimates of human intake. The authors made it clear
that chemical structure is to be used only as a guideline for testing
decisions and that such use of structure-activity analysis is intended as a
guide to the acquisition of data, not as a substitute for data.
307
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AN AUTOMATIC PROCEDURE FOR ASSESSING POSSIBLE C - CIN~ENIC
ACTIVITY OF CHEMICALS PRIOR TO TESTING
-
( DEHN AND HELMES, 1 9 7 4 )
This scheme uses structure-activity relationships to predict
carcinogenesis. mere is no exposure element. The corresponding exposure
element has been described by Gori (1977~.
me procedure incorporates the collective knowledge of a panel of
experts and attempts to automate the key features of that knowledge to
select candidate compounds for carcinogenicity testing. The basis of the
procedure is an activity tree constructed so that more specific details of
chemical structure (as related to carcinogenicity) are applied at each
decision point in the tree. This subdivision of structures continues until
an end group (called a node) containing compounds of closely related
chemical structure is identified. An estimate is then made of the
probability that the chemicals in a node are carcinogenic and of the
relative potency of each. Reflecting the expertise of the panel,
construction of the tree concentrates on the following groups of chemicals:
naturally occurring substances; nitroso, hydrazino, and ado compounds;
polycyclic aromatic hydrocarbons; aromatic amines; and inorganic compounds.
Although structure-activity relationships can be useful in setting
priorities for carcinogenicity testing, the accuracy of analysis of such
relationships in predicting carcinogenicity has not been verified. If the
decision tree could be compared with test data generated since the scheme
was completed, its utility could be better assessed. Exceptions within a
given node (i.e., negative compounds within a carcinogenic chemical class)
are extremely instructive and should serve as a cautionary guide when one
attempts to apply analysis of structure-activity relationships in too broad
a manner.
TOXICOLOG ICAL PRI NCIPLES FOR THE SAFETY
OF DIRECT FOOD ADDITIVES AND COLOR ADDITIVES USED IN FAD
(U. S . DEPARTMENT OF HEALTH AND HORN SERVICES, 1982)
This scheme was developed to establish priorities (and extent) for
toxicity testing of direct food additives.
Chemicals are divided into three categories of suspicion based on
structure-activity considerations by following a short decision tree. A
suspicion category is combined with exposure information to define a level
of concern (I, II, or III). Once the level of concern is determined, tests
may be required. Results of tests already done are placed in three
categories (well done; not well enough done, but usable to some degree as a
"core" test; and unusable). On the basis of this further information,
additional testing may be required.
308
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Toxicity is not estimated quantitatively, so there is no quantitative
assessment of uncertainty for it. There is judgmental consideration of
uncertainty (specification error) in the evaluation of toxicity tests in the
literature.
There is a discussion of tests for each level of concern and for various
combinations of concern and test information.
RANKING OF ENVIRONMENTAL CONTAMINANTS FOR BIOASSAY PRIORITY
(GORI, 1977)
The purpose of this scheme is to estab~ ish, on the basis of exposure ~ a
priority ranking for chemicals to be tested in a carcinogenicity bioassay.
All chemicals in commerce are considered by the scheme. Total intake of a
chemical by a given route is estimated for all members of a population group
with similar exposures, and intake is then summed over population groups and
sources of exposure. Intake by route is combined with probability of
carcinogenicity and expected potency to produce a ranking index that, in
theory, reflects the expected annual number of cancer cases.
The scheme depends on the quantitative prediction of carcinogenic
activity from structure-activity comparisons (see Dehn and Helmes, 1974~.
This requires the identification of substructures, derived from known
carcinogens, to which activity indexes can be attached--a process that
requires expert opinion. A chemical of unknown carcinogenic potential is
then inspected for such substructures, and an activity value is ascertained
on the basis of their presence.
Exposure assessment takes account of chemical production and use, but
not disposal or discharges explicitly.
Although it may not be clear from the text, the scheme estimates an
uncertainty factor or confidence range for every variable. One notes and
keeps track of the route of exposure and maintains an "audit trail" to the
information in the data base.
Deriving an exposure estimate for a chemical might require up to a
person-day of effort, on the average. Considerable subjective input is
required.
PRIORITY-SETTING OF TOXIC SUBSTANCES FOR GUIDING
MONITORING PROGRAMS (KORNREICH ET AL., 1979)
This system, prepared for the Office of Technology Assessment by Clement
Associates, is designed to compile a priority list for selecting potentially
toxic chemicals for monitoring in food.
309
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The criteria used in developing 32 existing priority lists of toxic
chemicals are examined, and criteria developed for ranking chemicals on the
basis of their likelihood of endangering human health through contamination
of the food supply. Three preliminary lists of possible food contaminants
(organic substances, inorganic substances, and radionuclides) are compiled.
Data on each chemical on these lists are assembled and used to assign scores
to each chemical for various factors. Scores for the factors are combined,
and the combined scores are used for ranking the chemicals on the three
lists.
Selection criteria include both exposure and toxicity factors. Weights
are assigned to reflect the relative importance of each criterion and to
allow the total score to be a measure of the overall propensity of a
chemical to contaminate foods. The individual score for each factor is
_ _ _ and the weighted scores are added. The
total exposure score and the total biologic score are each adjusted to a
maximum of 50 points and summed to allow for a possible total of 100 points.
multiplied by the assigned weight,
This system is designed to use quantitative information, with
considerable reliance on expert opinion for the assigning of scores. For
toxicity factors, a score of 0 is assigned for negative results and for
absence of data.
No cost estimates are given for this system, which was intended for
one-time, rather than repeated, use.
RANKING CHEMICALS FOR TESTING: A PRIORITY-SETTING
EXERCISE UNDER THE TOXIC SUBSTANCES CONTROL ACT
-
(NISBET, 1979)
This scoring system was developed to set priorities for testing
chemicals under the authority of the Toxic Substances Control Act. The
scheme is intended for application to chemicals in commerce that are not
covered by other statutes. Drugs, cosmetics, food additives, and pesticides
are excluded, unless they also have other uses. Also excluded are chemicals
with an annual production volume of 1,000 lb or less. The system is
intended for chemicals already in commerce at the time of compilation of the
TSCA Inventory, which now defines "old" chemicals for the purposes of the
statute. Because the Inventory did not exist when the first testing
recommendations were required by the statute, the system was originally
applied to a list of chemicals derived from lists of chemicals of high
production volume or previously reported toxicity. Thus, the initial
"universe" of chemicals was limited to chemicals already identified as of
potential concern or nominated for inclusion by Interagency Testing
Committee (ITC) members or other experts.
Of 24 priority lists reviewed, 19 were used as a basis for the initial
compilation of compounds. Noncommercial chemicals were then eliminated.
310
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Chemicals that were not on the U.S. ITC list were designated to be
eliminated from the list, but were screened initially and were included if
nominated by the expert panel. Later screening evaluated use and eliminated
substances already regulated under some statute other than the TSCA.
These initial screening steps resulted in a list of approximately 900
chemicals for scoring. ITC divided the scoring process into two discrete
phases--potential exposure and biologic effects. Screening and scoring of
biologic effects were postponed until potential exposure was evaluated. _
following factors were used in the first stage of exposure scoring:
· General population exposure--number of people exposed, frequency of
exposure, exposure intensity, and penetrability.
· Quantity released into and persistence in the environment.
· Production volume.
· Occupational exposure.
Some 330 chemicals were then selected from the list for biologic
scoring. The TSCA requires that ITC give priority to compounds that are
known or thought to cause or contribute to cancer, gene mutations, or birth
defects. Seven factors were selected for scoring on biologic activity:
Carcinogenicity.
Mutagenicity.
· Teratogenicity.
.
Acute toxicity.
Other toxic effects.
· Ecologic effects.*
· Bioaccumulation.
Because ITC seeks to identify chemicals that require testing, rather
than simply scoring compounds for known biologic activity, it was decided
that the biologic scoring system should have two independent components--a
measure of known biologic activity and a measure of the need for further
testing. These components provided the basis for the biologic scoring
system, as follows:
*Note that this scheme and its variants (Nisbet, 1979; Ross and Lu, 1980)
are designed to set priorities among chemicals for potential effects on the
environment, as well as on human health.
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It is probable that further scrutiny would follow a classification of
a chemical as a medium carcinogen; the assignment of 49 units for the
cost of regulatory error may overstate the cost of this misclassificat-
ion. With further scrutiny, there is some chance that the chemical in
question would be correctly classified, with eventually a lower cost to
society. The cost of this scrutiny in further testing might be $100,000
- 500,000 (less than if the chemical had been classified as high). Thus,
if the chemical is truly nontoxic, but is misclassified as medium, the
cost of the mistake might be a little more than 0.1 unit ($100,000),
suggested in Table E-2. Thus, we modify the costs of a regulatory error
when a chemical is classified as a medium carcinogen, as shown in Table
E-3.
Thus far, exposure has been assumed to be known and to be
proportional to production. Exposure has been estimated to range over
about 6 orders of magnitude. Furthermore, exposure often is fairly
independent of production. Taking into account a range of 6 orders of
magnitude in exposure and a range of 7 orders of magnitude in toxic
potency, a hazard index of the product of toxicity and exposure would
range over 13 orders of magnitude. At the same time, the link between
regulatory action and hazard classification becomes more complicated and
more diffuse.
A more complicated example of misclassification occurs when a
chemical is correctly classified as having medium toxicity, but
erroneously classified as having high exposure when in fact it has low
exposure. Is the chemical likely to be regulated on the basis of this
misclassification? Hardly. Before regulation, its exposure is likely to
be studied more carefully and (it is hoped) sufficiently well to correct
the misclassification of exposure. Because the exposure category is 3
orders of magnitude wide, this discovery is fairly likely.
Thus, the main cost of classifying exposure too highly is the extra
cost (ultimately found to be unnecessary) of learning that the chemical
belongs in a lower exposure category.
Now consider a chemical, correctly classified as high in toxicity,
but erroneously classified as having low exposure when it actually has
high exposure. Would such a chemical receive no further attention, on
the basis of its erroneous exposure classif ication? Once a chemical is
classified as having high toxic potency, it would receive further
attention, even if currently classified as having low exposure. With the
further attention, the erroneous classification of exposure would have a
good chance of being correctd. The main cost of this misclassification
is not the cost of research on exposure, which is warranted in this case,
but the cost arising from the chance that the error in exposure would not
be corrected through investigation.
Similar reasoning applies in the case of a chemical correctly
classified as being medium in toxicity, but misclassified as to
exposure. Too high a classification of exposure leads to unnecessary
research on exposure, whereas too low a classif ication leads to a chance
that research will not correct the error. Chemicals classif fed as having
medium toxicity are assumed to receive further attention.
372
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TABLE E-3 Cost of Regulatory Error in Terms of Social Benefit
per Average Chemical under Market Conditions, b (qm)
Cost, biqm)
Estimated t1 t2 t3
Toxicity
0 0.05 99
tl
t 0~4 0 25
-2
t3 le O O e 95 0
373
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Further attention is more likely to be devoted to these chemicals
than in the previous case, because less attention will probably be
devoted to a chemical classified as having medium than high toxic potency.
Taking these ideas into account, we might arrive at a table of
regulatory error, R(t,t), as shown in Table E-4. The underlined numbers
correspond to medium exposure and correspond to the entries of Table E-3,
with some modification.
The obvious thing to note in Table E-4 is the large range in the
costs of false-negatives, which appear above and to the right of the
diagonal whose values are zeroes. This range is due to the range of 13
orders of magnitude in hazard. The range of regulatory false-positives
is about 7 orders of magnitude, which is less than the range in hazard
because of the way false-positive and false-negative costs are defined,
in comparison with benefit, bigm). However, the range is still
enormous. Moreover, the cost of the largest false-negative (99,999) is
enormous, compared with the cost of the largest false-positive (0.8), and
probably much larger than most people would think realistic.
What might lead to overstating these ranges? Consideration of the
answers to this question leads to examination of two assumptions:
exposure is proportional to production, and a classification of medium
toxicity leads to some control. These assumptions may decrease the
differences between false-negatives and false-positives.
The "average" chemical is assumed to have market-determined
production, qm, with a net benefit, balm). Consider what happens
when qm also ranges over 6 orders of magnitude and, with it, net
benefit. In the simplest case, exposure is proportional to production,
and regulation follows directly from classification. The matrix of error
costs is similar to Tables E-2 and E-3, where the variation in bum)
and qm, from high to low production, scales everything up and down.
An overestimate of exposure is also a mistake in overestimating balm),
and these mistakes cancel out, as long as costs of mistakes are expressed
in terms of b~qm).
In another simple case, benefit, biqm), and production, qm, are
fixed and exposure still varies over 6 orders of magnitude. This case is
shown in Table E-4. A more realistic case has costs of regulatory error
intermediate between the values for the extreme cases shown in Table E-4.
The main reason for the high relative cost of the largest
false-negative in Table E-2 (99) is the assumption that there should be
some regulatory control for medium carcinogens. The control considered
was a restriction of production to about 50% of that determined by the
market. With the typical concavity of the benefit curve (which follows
from typical supply-and-demand schedules) and the range of 3 orders of
magnitude in toxic potency, this led to the asymmetric structure of Table
E-2.
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TABLE E-4 Expected Cost of Regulatory Error, as Modif fed by Expected
Reaction to Misclassif icationa
True Classification
Estimated
Classif i- eltl e2t1 e3t1 elt2 e2t2 3 2
cation
elt3 e2t3 e3t3
eltlO0 0. 05 0 0. OS 99 0.05 99 99, 999
e2t
e3t1
e t0.70.7
1- 2
0 00. 05 0 0. 05 99 0. 05 99 99, 999
0 00 0 0.05 99 0.05 99 99, 999
0.7 0 0.40 40 0.5 40 40, 000
e2t2 0 ~ 7 0 7 0 7 0 ~ 20 10 0. 5 10 10, 000
e3t2 0 7 0~7 0.7 0.20.1 0 0.5 5 5,000
elt3 0.8 0.8 0.8 0.40.4
0.2 0 2 200
e t 0.8 0.8 0.S 0.4 0.4 0.2 0.1 0 100
2 3
e3t3 0.8 0.8 0.8 0.4 0.4 0.2 .0_1 0.1 0
- exposure class; t = toxicity class. Subscripts: 1 = low or non-;
2 = medium; 3 - high. Underlined numbers correspond to medium exposure
and correspond to entries of Table E-3, with some modification.
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But there is another, probably more realistic, scenario in which
chemicals classified as of medium toxicity may be subjected to some
control. For the same production, more careful handling and use might
halve exposure at a management cost that is low relative to the benefit.
To have some control for medium toxicity, it is not necessary to posit
c2(q) with a slope of about 10% of that of bigm) (see Figure E-4.
Suppose the slope of c2(q) is only 1% of that of balm), instead of
10~. This assumption implies very little restriction in production, but
it could imply large reductions in exposure per unit of production by
restricting use and adopting stringent handling requirements. With this
change, we can revise Table E-2 to Table E-5. Again, consider the cost
of various cases of misclassification:
~ R(tlt3~. Because high toxicity is 1,000 times more than
medium toxicity, the slope of c3(q) is only 10 times that of balm).
Classifying a chemical as nontoxic when it has a high toxicity leads to a
false-negative regulatory cost of lOb~qm) - bigm) = Album) (upper
right corner of Table E-5 in terms of benefit from production set by
market conditions).
~ R(tlt2~. If a chemical is classified as nontoxic when it is
actually medium, it is possible to halve the exposure at a small cost
(say, 0.1%), relative to b~qm). The cost of regulatory error is
[b~q ~ = c2(qr) - O.Ollb~qm) - b~qm) - cfqm)~. Because
c2(qr) is half c2(qm), the cost of this false-negative is 0.004
unit of balm).
O R(t2t3~. If society acts directly on a chemical classified
as medium when it is actually high, the benefit is bum) - c3(qr) -
O.OOlbigm), or balm) - 5 - 0.001 balm). With correct information,
the chemical would be banned, with zero benefit. So the cost of this
false-negative is O - (-3.999) = 3.999.
· R(t2tl). If a chemical is classified as medium when it is
actually nontoxic, the benef it is b (qm) - O . OOlb (qm); it could have
been bm. The cost of this false-positive is 0.001.
0 R(t3t2~. If a chemical is classified as of high toxicity
when it is actually medium, it is banned, with zero benefit, whereas we
could have halved the exposure, at production qm, with a benefit of
bum) - c2(qr) - 0.001 bum) = 1 - 0.005 - 0.001 = 0.994b~qm).
The cost of this false-positive is 0.994biqm).
· R(t3tl). If a chemical is classified as highly toxic when
it is actually nontoxic, it is banned, with zero benefit, whereas we
could have had the benefit, berm), with no health cost. Therefore, the
cost of this false-negative is b(gm) - 0 = balm).
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TABLE E-5 Cost of Regulatory Error Due to Misclassification of
Toxicity in Terms of Social Benef it under Market Conditions, b (qm)
Cost, bedim)
t1 t2 t3
Estimated
toxicity
t1 00.004 9
t2 0.0010 3999
t3 10.994 0
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Table E-5 was Maculated on the assumption that exposure (unless
separately controlled) is proportional to production and b~qm) is
proportional to qm. Now we can take into account the idea that
exposure and production are not always proportional. Suppose that for
high-exposure chemicals the proportionality between exposure and
production is twice that for medium-exposure chemicals, and suppose
further that for medium-exposure chemicals the proportionality between
exposure and production i s twice that for low-exposure chemicals. In
other words, high-production chemicals tend to cost less per pound, and
the assumption is that the market benefit per pound of production volume
is half that for medium-production chemicals and one-fourth that for low-
production chemicals. This assumption leads to Table E-6. The false-
negative section (upper right portion) is revised, but the false-positive
portion is unchanged. Most of the false-positive costs are associated
with research to develop a chemical before it is regulated, and these
costs are limited to 1 unit; the total benefit having been foregone, the
chemical is erroneously banned.
It is difficult to assess regulatory costs resulting from
misclassification of a chemical with regard to exposure or toxicity.
But, although the above analysis can be refined, some features of the
structure of error costs are discernible. It seems reasonable for the
costs in the upper right portion to be asymmetrically larger than those
in the lower left portion--perhaps as much as 20 times as large. This
indicates that the social cost of underregulating a chemical is much
greater than that of overregulation. Exposure clarification is clearly
important, but it does not play a role entirely symmetric with that of
toxicity classification, as the simple concept, "hazard equals exposure
times toxicity," might suggest. The reason for the asymmetry is that
exposure tends to be proportional to the benefit of a chemical, whereas
toxic potency is an inherent property of a chemical and does not vary
with production, benefit, or exposure. An implication of this difference
is that, for a given health effect, information on toxic potency is
permanent or changes only as science improves, whereas correct
information on exposure is more dynamic and changes as production
responds to market changes and technologic advances.
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TABLE E-6 Regulatory Error Due to Misclassif ication of Exposure
and Toxicity
True Classif ication
Estimated
Classifi
cation1 12tle3t1 elt2 e2t2 e3t2 elt3e2t3e3t3
eltl000 0,002 0.004 0.008 4.5918
e2tl000 0.002 0.004 0.008 4.5918
e3t1 0 0 0 0.0015 0.003 0.006 4.5 8 16
elt2
e2~2
0.7 0.7 0.7
0.7 0.7 0.7 0.2
0 0.01 0.04
4 8
00.012 4 8
3t2 0 7 0.7 0.7 0.20.101.8 3 6
elt3
e2t3
0.8 0.8 0.8 0.4 0.4 0.200.01 0.05
0.8 0.8 0.8 0.4 0.4 0.20.10 0.01
e3t3 0.8 0.8 0.8 0.4 0.4 0. 2 0.1 0.1 0
a e = exposure class; t = toxicity class.
non-; 2 = moderate; 3 = high.
379
Subscripts: 1 = low or
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APPENDIX F
DIFFERENCES BETWEEN PART 1 AND PART 2
The stated objectives of the Committee on Sampling Strategies and the
Committee on Toxicity Data Elements differed from those of the Committee
on Priority Mechanisms. Accordingly, the concepts and practices used by
the committees to achieve the two objectives were different:
· The study included an examinination of the extent of toxicity
testing of chemicals to which humans are exposed and methods of selecting
chemicals for testing. The committees were thus assigned different
aspects of the same problem: evaluating toxicity testing for chemicals
of concern to NTP. The Committees on Toxicity Data Elements and Sampling
Strategies devised a method to assess the current state of toxicity
information used to determine health hazard and to estimate additional
needs for toxicity testing. The Committee on Priority Mechanisms
developed a design approach for priority-setting systems and applied that
approach to a demonstration system for the select universe defined by the
Committee on Toxicity Data Elements.
· The Committee on Toxicity Data Elements identified a list of test
types that served as a basis for examining the adequacy of past toxicity
testing and estimating current testing needs. The committees acknowledge
that under a variety of conditions it would not be necessary for all such
tests to be done. For example, although it is useful to have information
on chronic toxicity for a specific substance, the presence of positive
data from a well-conducted subahronic study might obviate the development
of any further information on chronic exposure. A need would still
remain to establish a mechanism for deciding which tests and which
substances should be examined and which ones would be given a higher
priority. The Committee on Priority Mechanisms examined this issue.
· The select universe defined by the Committee on Toxicity Data
Elements was fixed once the sample was taken so that, after sample
analysis, useful estimates for the universe could be made. The universe
of substances that the Committee on Priority Mechanisms considered,
however, by definition is constantly expanding as more substances with a
potential for human exposure are identified.
· Working documents developed and used by the Committee on Toxicity
Data Elements were designed to assess the status and quality of
toxicity-testing information. The dossier concept adopted by the
Committee on Priority Mechanisms is intended to provide an assessment of
exposure and toxicity. The approach of the Committee on Sampling
Strategies and the Committee on Toxicity Data Elements results in an
estimation of toxicity-testing frequency, adequacy, and needs based on a
retrospective analysis of existing information. The approach of the
Committee on Priority Mechanisms results in a priority-setting framework
that could be useful in determining which chemicals to test and which
tests would yield the most informative data.
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· me select universe of chemicals used in this study contained, by
design, substances with a potential for human exposure. A sample was
drawn from this select universe by the Committee on Sampling Strategies
for use by the Committee on Toxicity Data Elements in its determination
of toxicity-testing needs. Although the degree of potential human
exposure was used in the determination of testing needs, it was not a
determinant in selecting the sample of substances. In contrast, the
Committee on Priority Mechanisms suggests procedures that use information
on the degree of potential human exposure early in the chemical selection
process.
· For each substance in its sample, the Committee on Toxicity Data
Elements searched comprehensively for and nonselectively used all
. . . . . . . . . . . · · . . . . · ~
information that might assist It In aetermlnlog the testing neeas For
that substance. The Committee on Priority Mechanisms was selective in
applying information to each of the various stages of its priority-
setting system.
· Analysis of information was approached differently in each
activity. The purpose of the Committee on Toxicity Data Elements was to
determine the type and quality of available data, rather than review
existing assessments of toxicity. These determinations were based on the
expert judgment of committee members. The Committee on Priority
Mechanisms devised an approach to making assessments of public-health
concern as part of a system to select chemicals for testing. This
approach explicitly provides for estimating the degree of uncertainty in
the assessment.
· Finally, the Committee on Toxicity Data Elements and the Committee
on Sampling Strategies examined available information to determine
whether there is enough to conduct at least partial health-hazard
assessments. The Committee on Priority Mechanisms provides a framework
for using the information to conduct such assessments.
382
Representative terms from entire chapter:
toxicity data
