EPA/530-SW-86-005 f
•• • *.';. \^ . V
OSWER POLICY DIRECTIVE NO. 9551.00-1A
LAND DISPOSAL BAN VARIANCE PETITIONER'S GUIDANCE MANUAL
DRAFT
Office of Solid Waste
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, D.C. 20460
February 1986
-------
-------
530-SW-86-005.A
SPECIAL NOTE
This draft guidance manual is based on a proposed rule,
the approach and content of the final version of the guidance,
when issued, will be dependent on the approach promulgated
in the final Land Disposal Restrictions Rule. Promulgation
of the first phase of final land disposal restrictions is
scheduled for November 1986.
-------
-------
Land Disposal Ban Variance
Petitioners Guidance Manual
CONTENT
I. Introduction
II. Waste Analysis
III, 1st Tier Analysis - Screening Factors
a. Approval or Rejection Criteria
b. Approval for a 2nd Tier Simplified analysis
IV. 2nd Tier Analysis - Simplified Site Analysis
• •
a. Objectives • *
b. Health-based Threshold Models, or Other
Simplified Models
c. Data Requirements
d. Point of Exposure
e. Analysis and Decision Criteria
V. Exposure and Population Analysis
a. Exposure Assessment
b. Population Characterization
c. Risk Management Factors
VI. 3rd Tier Analysis - Elements of a Detailed Site Analysis
a. Objectives
b. Petitioner Conference
e. Components
d. Format
e. Technical Assistance
f. Related Guidance Documents
V. Summary of the Conditions of an Approved Petition
Appendix I Screening Factors
Appendix II Proposed Land Disposal Restrictions
Appendix III Agency Risk Assessment Guidelines
-------
-------
I. Introduction
This guidance manual provides a. basic description of the
requirements for petitioning the Agency for removal of
"restrictions placed on the land disposal of any hazardous
• • ' •
waste under Section 3004 (d), (e), or (g) of the Resource
Conservation and Recovery Act (RCRA). To obtain approval for
i> • ' . • • . • . • •
a petition, it must be demonstrated that land disposal is a
management practice that will be protective of human health
and the environment. To be protective. Section 3004 of RCRA
w
requires that the petitioner demonstrate "... to a reasonable
«
degree .of certainty, that there will be no migration of
hazardous constituents from the disposal unit or injection
zone for as long as the wastes remain hazardous." This manual
will describe the process by which such petitions will be
prepared and submitted to the Agency for review and approval.
The November 8, 1984 amendments to RCRA provide the
Agency a basis on which to restrict hazardous wastes from
land disposal. The restriction decision is not based on an
absolute prohibition of land disposal of hazardous waste but
takes into account the relationship between concentrations of
'Appendix VIII constituents in waste leachate and the risk
they may present to a potentially exposed population. The
Agency has developed a decision mechanism for land disposal
restrictions that accounts for the toxicity of a waste, and
the fate and transport of waste leachate as it may affect
human or environmental exposure. A general description of
-------
this mechanism will be outlined below such that the petitioner
may understand the basis of the restriction decision and also
become aware of the possible avenues available for pursuing
a petition demonstration.
' t
The performance standard of no migration for as long as
the wastes remain hazardous is opsrationalized by allowing
migration of waste constituents at or below concentration
levels in all media (surface water, ground water9 and air)
that are protective of human health and the environment.
The establishment of concentration levels in each media that
«
_
are protective of human health and the environment is based
on toxicological data, in conjunction with established Agency
protocol for analyzing toxicological data. The reader may
refer to Appendix III for a general description of Agency
protocol used to evaluate toxicolgical data. A concentration
level that is found by the Agency to be protective of human
health is referred to as the Reference dose (RfD) for
noncarcinogens (threshold toxicants) and as the risk-specific
dose (BSD) for carcinogens (non-threshold toxicants). The
RFD corresponds to a dose that is reasonably protective of
human health when exposure is chronic. The RSD corresponds
to a dose that presents a specific probabiity of cancer over
and above the normal background probability of cancer for an
individual over a lifetime, within a range of 10~4 to 10~?.
The RfD and RSD underpin the restriction decision process.
They are used to calculate Screening Levels (SL) that determine
whether a waste having a specific leachate concentration
-------
is restricted from land disposal or not. The Agency does
not use the concentration of the constituents in the waste
• ' '..'-..
itself to compare with the SLs. Instead the Agency uses the
concentration of the constituents in the waste leachate to
compare with the SL(s). The reader should refer to "Test
Methods for the Evaluation of Solid Waste, Physical/Chemical
Methods", SW-846 for a discussion of waste leachates and the
extraction and measuring techniques used to determine concen-
tration levels of Appendix VIII constituents. A waste is
restricted from land disposal whenever its leachate contains
t
any one or more Appendix VIII constituents in concentrations
that exceed that calculated SL for that respective constituent.
The SL(s) are determined by "backcalculating" from
concentrations that are protective of human health, at the point
of exposure to a point or zone that is located immediately beneath
or adjacent to the disposal unit. Backcalculating involves
reversing the normal direction of fate and transport models that
usually start with the source concentration and calculate the
fate and transport of a substance to determine its concentration
at a point of exposure. Thus the end result of backcalculation
is a maximum waste or leachate concentration for each Appendix
VIII constituent. The backcalculation is performed for each
Appendix VIII constituent for each media. Thus for a given
Appendix VIII constituent, there will be two SL(s), one for air
and one for water. Whichever SL for a given constituent is
lowest will be used as the maximum allowable concentration in
the waste (for air) or in the leachate (for water) for land
-------
4
disposal. Owner/operators and/or generators whose waste
leachate has concentrations of Appendix VIII constituents at
or below the lowest SL need only certify that this is so.
Details for certification will be discussed below. Those
owner/operators who exceed.any SL for any constituents in
their waste leachate must either comply with applicable treat-
ment standards, petition for a variance, or stop land disposal
of the waste altogether. '
The fate and transport models that are used to backcai-
culate SL(s) from RfD(f) and RSD(s) are generic by design.
The models incorporate a universal facility type that is
representative of the various types of facilities defined as
land disposal units. In addition the model incorporates a Monte
Carlo approach for simulating the range of anticipated disposal
scenarios. This approach accommodates variation in environmental
settings, the uncertainties in specific chemical properties,
and the range of engineered system releases from land disposal
units. Rather than specifying a single value for each input
parameter to the model to represent a reasonable worst case,
.the Monte Carlo simulation method involves a large number of
computer runs with values for each input parameter drawn from
data sets representative of the range and distribution of
possible values for each parameter. Moreover, where parameters
are dependent (correlated), the relationships are accounted
for in the simulation. The SL's thus derived are intended to
be protective of human health and the evnironment at all
disposal unit sites. i
The Agency is aware that the generic model approach will
not always account for the multitude of variations that may
-------
exist among actual existing or future land disposal units and
the environmental settings they may be operating in. The generic
screening levels computed by the model are based on the level
corresponding to the 90th percentile of the range of hydrogeologic
scenarios arranged from favorable to least favorable cases. Thus,
the generic value may be more conservative than necessary for sites
that fall below the 90th percentile. Thus, the petition process
allows the petitioner to demonstrate that the subject facility
will safely contain the waste of interest despite the results
of the generic model.; The petitioner may challenge the results
of the generic model on the basis of unique site-specific
factors and values not accounted for in the model.
The petitioner may not, however, challenge through the
petition process either the RfD or the estimates of carcinogenic
potency used by the Agency to calculate the RSD. (See Appendix
III). Any challange to the established RfD(s) or carcinogenic-
potency estimates must b@ presented to the appropriate office
of the Agency for review. The Agency will assess the merits
of any challenges to either an RfD or carcinogenic potency
estimates and any resulting revisions will apply across the
board to all Agency applications of the RfD and the RSD.
Essentially there are two approaches whereby a petitioner
may successfully obtain petition approval. They ares
(1) The leachate concentration of any Appendix VIII
constituent will never exceed the lowest back
calculated SL? based on an analysis of site
-------
specific data, and thus any migration that
does occur will not endanger human health.
(2) The leachate concentration of any one or more Appendix
VIII constituent will exceed the lowest applicable
SLs, yet because of unique site specific factors,
will not endanger human health.
The first approach would be based on unique natural physical
or biologic phenomena not completely accounted for in the
generic Screening Level models. In addition to natural phenomena,
engineered systems maybe considered for their efficacy in
controlling constituent migration to the extent that they are
effective over the time the waste remains hazardous. In
summary, the petitioner must demonstrate that as a result of
natural chemical and physical processes at the site, hazardous
constituents are immobilized, diluted, or degraded by the
time they reach points of potential exposure such that human
health is protected.
The second approach may also be supported by evidence
mentioned in the first approach as it may modify exposure to
existing or potential populations in proximity of the site.
In addition, the petitioner may present information concerning
the nature and size of the potentially exposed population,
and toxicological data relevant to potential exposure scenarios
to demonstrate that human health is protected. Under this
approach, the petitioner would be responsible for demonstrating
that an exposure scenario whereby the leachate constituent
concentrations of the waste would result in concentrations at
the potential point or points of exposure exceeding the
-------
established RfD or RSD would still be protective of human health.
f This approach requires that a site-specific risk management
decision be made regarding the degree to which the RfD or RSO
€ •
could be exceeded for a particular site and waste stream.«
For the RSDff the Agency is willing to consider departures from
the 10~6 level of individual risk to a maximum of 10~4 based
on considerations of the size and nature of the existing or
future exposed population. For the RfD, the Agency will consider
situations in which site specific exceedances may be reasonable
given the size and nature of the existing or potential population/
the severity of the disease outcome, and the reversibility of
any toxic effects.
The guidance manual describes a number of avenues open
to the petitioner for demonstrating to the Agency that a
particular waste should be approved for site specific land
disposal. Recognizing that such a demonstration can be
extremely complex? depending Upon the characteristics of the
waste and the disposal unit site, the Agency has developed a
flexible process that identifies those situations that require
. a relatively simple demonstration relying on data readily
available to the petitioner, and also identifies those more
complex situations that require a more detailed analysis and
potentially extensive site-specific data collection to obtain
petition approval.. The petitioner will be able to readily
determine whether he or she qualifies for a simple analysis or
-------
8
must perform a more detailed site analysis. Using this guidance
manual, the petitioner will also be able to determine the
likelihood for approval of a petition, or whether the combined
waste and site characteristics indicate that approval is
highly unlikely. The petitioner should be able to quickly
determine the amount of effort required to obtain petition
approval, and decide whether another waste management
alternative is preferable.
This guidance manual will describe criteria that the
Agency will use to evaluate petitions and determine whether
an approval is justified. The decision will be based on the
Agency's evaluation of the performance of the disposal unit
combined with its location in meeting the standard of
performance stated in Section 3004 (d), (e), and (g) of RCRA.
The criteria have been developed to do the following?
1. Approve or reject a petition based on data and analyses
already available to the Agency?
2. Determine eligibiity for a petition based on minimum
data requirements;
3. Determine eligibility for a simplified site analysis;
4. Approve or reject a petition based on the results of
a simplified site analysis; -
5. Approve or reject a petition based on the results of
a detailed site analysis.
The evaluation criteria will consist of screening factors,
minimum requirements for data quality and quantity, use of
simulation models, and the use of health and environmental-
based screening levels. These criteria will be applied in a
tiered fashion, in which a petitioner can initially determine the
-------
depth of analysis required* If the petitioner is rejected in
the first tier (screening step), or in the second tier
(simplified site analysis)f he still has the option of
proceeding to a third tier analysis (detailed site or health
effects analysis). At each step in the process, the petitioner
can re-evaluate the decision to pursue the petition.
The following sections of this guidance manual describe
the components of each of the three tiers, and the decision
criteria to be used in evaluating petitions. Section II
discusses the waste testing and analysis requirements.
Section III outlines the. screening factors that constitute
the 1st Tier analysis. Section -IV describes the approach to
be used in the 2nd Tier, the simplified site analysis. Section
V describes the objectives of the Exposure and Population
Analysis, which is optional to a petitioner performing a 2nd
Tier analysis, and may be required as an optional component of
all 3rd Tier analyses. Section VI briefly describes the
components and scope of a 3rd Tier, detailed site analysis.
Additionally, a series of appendices are included to provide
perspective on the Agency's risk assessment and risk management
policies.
II. Waste Analysis
The petitioner must perform a waste analysis to determine
the presence and concentration of all Appendix VIII constituents.
Wastes containing any of these constituents are restricted from
land disposal in concentrations in excess of the applicable
-------
10
Screening/Treatment Levels. The petitioner must identify all
of the Appendix VIII constituents present in the restricted
wastes that exceed these levels.
The petitioner should perform the .waste analysis by using
•
sampling arid analyical methods described in "Test Methods for
the Evaluation of Solid Waste, Physical/Chemical Methods", SW-846,
insuring that representative samples are taken.
The petitioner may use other equivalent test methods that have
been approved by the Agency. The use of the Toxicity Characteristic
Leaching Procedure (TCLP) is required as a standard method
*
for characterizing waste leachate. Exhibit II-l displays the
process for applying the TCLP. The petitioner may also provide
additional data on the physical and chemical characteristics of
the waste, if such data is relevant to the type of demonstration
being performed.
Exhibit II-2 lists some of the data that the petitioner
may be required to provide, if he is performing a 3rd Tier
analysis. Exhibit II-2 also indicates the specific types of
data that should be necessary for a 2nd Tier analysis. Exhibit
II-3 is a suggested format for reporting the results of
the waste leachate analysis and the identification of chemical
constituents and their concentrations. The petitioner should
assure that the information included on this exhibit
describes the subject waste leachate accurately and completely.
If the petition is approved, it will be approved for a waste
that exhibits precisely the characteristics described on
-------
11
EXHIBIT H-l. TCLP FLCWCHSRT
WET WASTE SAMPLE
CONTAINS < 0.5 %t
NON-FILTERABLE
SOLIDS
LIQUID/SOLID
SEPARATION
0.6 - 0.8 urn
GLASS FIBER
FILTERS
LIQUID
STORE AT
4°C
REPRESENTATIVE WASTE
SAMPLE > 100 GRAMS
DRY WASTE
SAMPLE
.DISCARD •
SOLID '
SOLID-
SOLID
REDUCE PARTICLE SIZE IF> 9.5 run
OR SURFACE AR£A>3.1 on2
i.
TCLP EXTRACTION OF SOLID
0-HEADSPACE EXTRACTOR
REQUIRED FOR VOLATILES
LIQUID/SOLID SEPARATION
0.6 - 0.8 urn GLASS FIBER FILTERS
WET WASTE SAMPLE
CONTAINS > 0.5%
NON-FILTERABLE
SOLIDS
TCLP EXTRACT
LTCLP EXTRACT
ANALYTICAL
METHODS
LIQUID/SOLID
SEPARATION
0.6 - 0.8 urn
GLASS FIBER
FILTERS
LIQUID
STORE AT
DISCARD
SOLID
. TCLP EXTRACT-
-------
12
EXHIBIT II-2. WASTE INFORMATION REQUIREMENTS
(to be provided for each petitioned waste)
I Wast© Name: • .
*
2 List all applicable EPA Hazardous Waste .Codes (including F, K, Uf and P
code designations as outlined in 40 CFR.31, 32, and 33);
3 List originating industry and provide 3 digit SIC codes
I List all manufacturing process(es) that produce the waste:
5 List constituents of the waste (use commonly accepted compound names);
5 Complete the following sections pertaining to hazardous properties
for each waste and its constituent memberss
«
0 Is the waste considered ignitable using criteria outline in
261.21? (Y/N)
0 Is the waste considered corrosive using criteria outlined in
261.22? (Y/N)
• Is the waste considered reactive using criteria outline in
261.23? (Y/N)
0 Is the waste considered to exhibit the characteristics of EP
toxicity as outlined in 261.24? (Y/N)
» List the quantity, of banned waste as a percentage of the total waste
present in the disposal facility (weight basis):
3 List the respective length of time of disposal of each waste including
banned and non-banned in the facility (attach sheet separately):
} List the frequency of each waste (weight/unit time) received in the
facility on a daily, monthly, and yearly basis:
) Estimate the maximum quantity of waste to be received by the facility
(if there is no basis for estimation, list the design capacity of
the facility).
i List and discuss all pretreatment processes and their respective end
effects on the waste:
2 List and discuss all processes for handling and storage of the waste
and the important design specifications for each unit operations
3 If applicable, 'list the complete time of processing of the wastes
-------
13
EXHIBIT II-2 (Continued) REQOIRMENTS FOR PHYSICAL/CHEMICAL/
BIOLOGICAL CHARACTERISTICS OF THE WASTE AND EACH OF ITS
CHEMICAL CONSTITUENTS
i (information to be provided seperately for each waste and
for each component of wastes that are mixtures)
I Molecular Structure (attach diagram separately):
5 Molecular weight:
3 Density:
7 Phase (at STP):
J Viscosity:
) Boiling Point: ;
} Freezing Point:
L Solubility in polar solvent (water):
I Solubility non-polar solvent:
3 Plot solubilities (both solvent types) as a function of pH (range 2-12)
(attach graph separately):
i ^Dissociation constant:
5 Octahol/water partition coefficient:
5 Henry's Law constant:
7 Critical volume, temperature, anmd pressure:
3 Vapor pressure:
3 biffusivity (kinematic viscosity):
3 Thermal conductivity:
1 Biodegradation rate:
2 Oxidation rate:
3 Photolysis rate:
4 Bioacculation (bioconcentration) potential:
5 PEL (Permissible Exposure Limit):
6 *IDLH (Immediately Dangerous to Life and Health):
7 THV (Threshold Limit Value):
-------
Exhibit II-3 Generator Name
Waste Description
Appendix VIII Constituents
Concentration (reg/liter)
AverageMaximumMinimum
Standard
'Deviation
Number of
Analyses
-------
15
this exhibit. If ths waste that is being generated and
managed in a land disposal unit as a result of petition
approval does not exhibit the characteristics described on
this exhibit, the petition approval will be revoked. The
waste will no longer be eligible for land disposal, until a
revised petition is submitted and approved. Continued land
disposal of a waste that no longer qualifies for petition
approval is considered to be grounds for enforcement action
by the Agency.
Once the petitioner has completed the waste analysis and has
determined the presence of various Appendix VIII constituents
and their concentrations, he or she should determine which of
these constituents exceed the Screening/Treatment Levels. (See
Appendix II). These levels are published in various Federal
Register notices, corresponding to the proposed schedule for
restricting wastes from land disposal published in the
Federal Register on May 31, 1985. The petition must
address all Appendix VIII constituents that exceed these
levels. In some cases, there may be present in the waste an
Appendix VIII constituent for which no Screening/Treatment Level
exists, due to the timing of the development of these levels.
When this case arises, the petitioner may choose to include
these additional constituents in the demonstration, if he has
reason to believe that eventually the screening level that
'i
will be established would be less than the concentration in
the subject waste leachate. If the additional constituents are
included and the petition was approved, the waste could be land
-------
16
disposed, and no future petition would be necessary. The
petitioner may also choose to exclude these additional constituents,
if he estimates that the screening level eventually established
would not be exceeded by the level in the subject waste. If
. the petition was approved, there is the possibility that the
waste may be banned at some future time, due to the establishment
of different screening levels.
As an alternative to performing a full Appendix VIII analysis
of the subject waste, the petitioner may submit information to
the Agency that certain Appendix VIII constituents are not present
« _
in the waste, due to their absence from the raw materials used
in the process that produces the waste, and due to the manufacturing
process itself. The Agency reserves the right to require additional
analyses for specific chemicals that may be suspected to be present,
based on information already available to the Agency or similar
manufacturing processes and similar raw materials. If, upon
subsequent testing of the waste, it is determined that additional
constituents are present that were certified as not being present,
the approved petition will be revoked until such time as a revised
petition demonstration, that includes the additional constituents,
is completed and approved. Continued land disposal of a waste
with constituent concentrations that exceed applicable SL's con-
stitutes a violation of the operating permit and may result in
enforcement action.
For those wastes that contain a substantial number of
Appendix VIII constituents, the petitioner may choose to group
similar chemicals according to properties related to the rate of
-------
17
mobility and persistence in the environment. If such a
grouping can. be made? the petitioner may include in the
analysis only one chemical from any group that represents, in
. • ,
a reasonable fashion, the mobility and persistence of all of the
group members* In selecting an indicator chemical constituent,
the petitioner should consider the relative amounts in the
waste of the various group members. A chemical that is
similar to the other group members, but not present in a
concentration as high as other chemicals may not be a suitable
indicator for that group. Additionally, the petitioner should
consider the unique characteristics of the various environmental
media (air, ground water, surface water, and soil) at the
disposal unit site, in selecting a specific chemical as an
indicator for a group of like chemicals.
To use an indicator chemical approach based on chemical
and physical properties that relate to the wastes' mobility
and persistence, the petitioner must present reasonable
evidence to demonstrate that the grouping is justified. In
many cases, chemicals that belong to a generic group (i.e.,
solvents, polycyclic aromatics, metals, etc.) may have similar
chemical structure and may be expected to be transported in
air, soil, surface water, or ground water at nearly the same .
velocities. The petitioner will be required to present
reasonable evidence that minor variations in chemical structure
do not represent major variations in mobility and persistence.
-------
18
The petitioner should also consider possible synergistic
effects when using an indicator chemical to simulate the
mobility and persistence of a group of chemicals. .The Agency
will review, for reasonableness the petitioner's grouping and
selection of an indicator chemical. The Agency will refer
to the qualitative structure activity relationship between
the group members, various estimators of mobility and persistence
(e.g./ Henrys' law constant, octanol water partition coefficient,
etc.), and any other field monitoring or research data that
may establish a basis for grouping of chemical constituents.
The petitioner must be cautioned that the use of indicator
chemicals for performing the exposure analysis does not allow
the same type of grouping for performing the health effects
analysis described in Section V, should such an analysis be
performed. The health effects analysis must include the
effects on the exposed individuals of each chemical constituent
subject to the petition, not merely the indicator of mobility
and persistence which is used, to estimate potential exposure
levels.
The petitioner should include in the petition a concise
summary of the waste analysis and any grouping or selection
of indicators. This summary should identify specific chemicals
and their expected ranges of concentrations that will form the
basis for the 2nd Tier analysis. For the 3rd Tier analysis
-------
19
additional data may b® required, depending upon the nature of
the demonstration to be performed. At a minimum, some
estimation of the annual volume of the subject waste should
be made. This estimation may be based on historical production
rates projected into the future, or on the design capacity of
the disposal unit.
III. 1st Tier Analysis - Screening Factors
This section describes a series of screening factors
that the petitioner must consider prior to preparing a petition
demonstration under either the 2nd Tier or 3rd Tier analyses.
These screening factors are designed to indicate to the
petitioner the likelihood of obtaining petition approval
*
and the type and level of analyses required. Also, the .
screening factors identify certain decision points for the
petitioner in the demonstration, and identify decision criteria
that the Agency will use in evaluating petitions.
There are several purposes to be served by the use of
screening factors in the petition process. The Agency believes
that the statutory performance standard requires a positive
demonstration of safety before petition approval is justified.
'Therefore, the petition process must be capable of identifying
any site-specific features that would clearly be unfavorable
to petition approval. This early identification of unfavorable
features provides warning to the petitioner that ultimate
approval may not be likely, and that the petition may be ineligible
for a 2nd Tier analysis. The screening factors also will provide
-------
20
basic pre-requisites to a 2nd Tier or 3rd Tier analysis, in
describing minimum data and administrative requirements*
Additionally, the screening factors provide an objective and
systematic method for reviewing petitions received from generators
and disposal units across the country.
The screening factors that the Agency will use may be briefly
described as follows:
A. Approval Criteria
These criteria will allow the Agency to grant approval
to a petition immediately, with no further data or
analyses required by the petitioner; The petitioner will
'certify to the Agency that the approval criteria are met, based
on unique waste or site conditions or based on the results of
previous studies. The petitioner will be given written notice
of the approval following Agency review of appropriate information
already available to the Agency to corroborate the certification
of the petitioner.
B. Rejection Criteria
These criteria will identify situations that render a pro-
.spective petitioner ineligible for a petition demonstration.
If the petitioner cannot meet these criteria, the Agency will
•• i«
not commence review of the petition.
C. Eligibility for a 2nd Tier Simplified Analysis
These criteria will identify those petitions that are
eligible for a simplified site analysis, as described in Section
IV. Since a 2nd Tier analysis generally involves use of site-
specific data of reasonable quality that are already available
-------
21
to the petitioner or easily obtainable, and an analysis that '
involves the Screening/Treatment Level models, these criteria
will identify those sites that contain features that cannot be
analyzed with these models« Such sites may involve the use of
additional conservative assumptions as a means of justifying
the 2nd Tier analysis, or may require that a 3rd Tier analysis
be performed.
The screening factors and the criteria associated with
each are contained in Appendix I of this document.
*
IV. 2nd Tier Analysis - Simplified Site Analysis
A. Objectives • .
This section describes the requirements for completing
a simplified site analysis. The objectives of a simplified
site analysis are to determine on a site-specific basis, a
level or concentration in a waste that will not threaten human
health and the environment when that waste is placed in a land
disposal unit, and to make this determination in a comprehensive
way without requiring extensive data collection and complex
analyses. The simplified site analysis must rely on site-specific
input data already available to the petitioner or to the Agency,
or on data that should be readily attainable by the petitioner
from independent sources. Where adequate data is unattainable.
without an extensive or time-consuming site analysis, the use of
estimates and assumptions is acceptable, as long as the estimates
-------
22
and assumptions are reasonably conservative. The simplified
site analysis must rely on an analytical tool that is appropriate
for simulating the site's environmental conditions. The use of
the unmodified versions of the Screening/Treatment Level models
should constitute the most simplified analysis that would be
acceptable for a petition demonstration.
B. Screening/Treatment Level Models
The models that the Agency has developed for determining
the Screening/Treatment Levels may be used for a simplified site
analysis. The models Ihave been constructed so as to simulate a
generic disposal unit, and have built-in assumptions that
• . '
specify the generic site conditions relative to the hydrogeology,
topography, and climate. The petitioner may use either of the
models (air, ground water, and surface water) if he or she so
chooses. The models require certain specific input values for
hydrogeologic, topographic/ and climatic factors. The models
calculate an acceptable leachate concentration for each
constituent based on the appropriate human health criteria at
the point of human exposure. Using site-specific data, the
petitioner may run the models and establish site-specific
screening levels for each Appendix VIII constituent that is of
concern to the petition demonstration. Using the same back
calculation approach that established the nationally applicable
Screening/Treatment Levels, the petitioner may determine that
-------
23
approval is justified by comparing the actual waste constituent
concentrations to the site-specific levels.
As an alternative, the petitioner may use other simplified
models to simulate the behavior of the subject waste, using
actual waste constituent concentrations, and predict the likely
levels of each contaminant in the air, ground water, surface
water, and soil at any points of potential exposure* The use
of any other models requires adequate validation for the intended
application. This predicted exposure level would be compared
to the appropriate Rffc's and RSD's to determine whether petition
approval was justified.
C. Data Requirements
Regardless of the type of modeling approach employed by
the petitioner, the data requirements for a 2nd Tier analysis
should be similar. The simplified analysis should make maximum
use of site-specific data that is reasonably accurate, and.vthat
is already available to or easily attainable by the petitioner.
Much of the data that is required for a RCRA Part B permit,
especially the data required for establishing a Subpart P ground-
water monitoring program, is directly relevant to a petition
demonstration. In some cases, the models chosen may require some
additional data, or may require that the data be -re-formatted.
The Agency will accept reasonably accurate data or estimates to
satisfy these additional requirements.
-------
24
In reviewing the input data supplied by the petitioner for.
the 2nd Tier analysis, the Agency will apply a "reasonableness"
test. Using published sources of hydrogoologic, topographic,
and climatic data, in addition to any actual site data collected
by the Agency or State, the petition reviewer will determine if the
petitioner's data is reasonably accurate. .If any doubt exists
as to the reasonable accuracy of the petitioner's data, the
Agency will perform an appropriate sensitivity analysis of the
model results. If, in the opinion of the petition reviewer,
the results of the sensitivity analysis indicate that substantially
different results may be obtained by varying the input data, the
petitioner may be asked for documentation to support the "original
data, the Agency may require that a 3rd. Tier analysis be performed
that includes additional on-site sampling and analyses and thorough
quality control, or the Agency may reject the petition due to
an unreasonable degree of uncertainty in the analysis.
The objective of a "reasonableness" test is to determine, on
a site-by-site basis, whether the petitioner's data is within the
range of typical values of measured parameters for specific
geologic, hydrologic, and climatic regions. The Agency will
review the petitioner's data to assure that it is consistent
with ranges of values in various published reference sources,
and that each factor is internally consistent with other factors
where a dependency relationship is expected to exist. Examples
of reference sources that the Agency may use are the following;
-------
25
1. Parameters and Variables Appearing in Repository
Siting Models, NUREG/CR-3066? by J.W. Mercer, S.D.
Thomas, B. Ross 1982, U.S. Nuclear Regulatory Commission.
2.. Mercer, J.W., P.S.C« Rao, S.D* Thomas, and B. Ross.
"Description of Parameters and Data (and Typical Ranges
of Values) Useful for Evaluation of Migration 'at
Hazardous Waste Management Facilities, letter report
to U.S. EPA under Contract No. 68-01-6464, 1982.
3. Lyman, W.J., W.F. Reeh1 and D.H. Rosenblatt. Handbook
of Chemical Property Estimation Methods - Environmental
Behavior of Organic Compounds. McGraw-Hill, Inc. 1982.
D. Point of Exposure
It is necessary for the petitioner to establish a point or
points.of potential human exposure in each environmental media
where migration could occur. For the purpose of a petition
demonstration, the potential exposure points are at the boundaries
of the disposal unit, unless the petitioner can establish
effective long-term controls over an area beyond the boundaries
of the disposal unite Any legally enforceable restrictions on
•the use of any on-site water resources within the property
boundary where the disposal unit is located would justify a
point or points of exposure at the property boundary. An act
of the state legislature that places permanent restrictions on
the use of any water resources within a carefully defined area
beyond the property boundary would allow the petitioner to
-------
26
establish a point or points of exposure at the limits of this
expanded area of effective control. Wherever the point or
points of exposure are ultimately established, the petitioner
must use the actual linear distance from the center of the
disposal unit to the closest point of potential exposure in
the simplified modeling analysis.
In considering air migration, the point of potential exposure
for direct inhalation during the operating and closure periods
of the disposal unit would be at the surface of the impoundment,
landfill cell, waste pile, or land treatment unit, unless access
to the disposal unit by any unauthorized persons is prevented
by an adequate security system, and all authorized personnel
are adequately protected from air emissions. If security and on-
site- safety precautions are adequate, the point of potential
human exposure for direct inhalation may be established at the
limits of the area controlled by the security system. The
actual linear distance from the center of the disposal unit to
the closest point of potential air exposure should be used by
the petitioner in performing the simplified site analysis
under the 2nd Tier approach.
In performing a 2nd Tier analysis involving the Screening/
Treatment Level models, the distance to the point of potential
exposure is assumed to be 500 feet. In applying these models
to a site specific petition demonstration, the distance assump-
tion cannot be increased without adequately validating all
other model assumptions. The* balance of assumptions that is
-------
27
attained in each of the Screening/Treatment Level models would
be distorted by varying any one assumption, so that, model
results may not be consistent with other model applications.
The petitioner may wish to demonstrate that actual site condi-
tions deviate from some of the assumed conditions of the
Screening/Treatment Level models. This is permissable as long
as all model assumptions are adequately validated for the
site-specific application.
If an existing source of drinking water, either a ground
water or surface wate? source, is within 500 feet of the dis-
posal unit, the petitioner should modify the Screening/Treatment
Level model to include the actual distance rather than the
assumed distance of 500 feet. Such a modification should not
require any validation, as long as the other assumptions of
the model are not changed.
E. Analysis and Decision Criteria
In performing the 2nd Tier analysis, the petitioner should
consider the possibility of human exposure to any of the subject
waste constituents in the air, ground water, and surface water.
Using the Screening/Treatment Level (S/TL) models, the petitioner
can determine a site-specific screening levels in the air, in
the ground water, and in the surface water for each constituent.
Comparison of the site-specific levels to the actual concentration
in the waste leachate allows a determination of whether or not
there are any threats to human health associated with land
disposal of the waste. If an indicator chemical approach was
-------
28
used for the fate and transport analysis, the petitioner must
consider the potential human health effects associated with
each chemical, not just the indicator. If no constituent
concentration in the waste exceeds the applicable site-specific
level/ the petition should be approved relative to potential
human health effects.
If the petitioner chooses not to use the screening level
models, other simplified models that simulate site conditions
can be used to determine the maximum concentration that may
occur at any points of-potential exposure. This maximum
concentration can be compared to the human health criteria
used in setting Screening/ Treatment Levels. If no constituent
concentration in the waste exceeds the applicable site-specific
. level, the petition should be satisfactory.
If the actual waste constituent concentrations exceed the
site-specific levels or result in predicted exposure in
excess of the RfD or risk-related dose for a carcinogen, the
petition should be rejected. If rejection is likely, the
petitioner may choose one of three possible alternatives. One
alternative is to accept the results that lead to rejection and
withdraw the petition. Another alternative is to perform a
site-specific health effects analysis. The third'alternative
is to perform a detailed site analysis, which also includes an
exposure and population analysis. The next section describes
the objectives and elements of an exposure and population
analysis.
-------
29
V. Exposure and Population Analysis
The petitioner has the option of performing an/exposure
and population analysis to support a petition demonstration.
The exposure analysis may allow for a reconsideration of a
number of exposure-related assumptions that are incorporated
into the screening level models that may not be applicable at
a specific site. An exposure and population analysis also
allows some'consideration of the degree of uncertainty involved
in the petition demonstration and allows for a more flexible
risk based management decision for petition approval.
*
The petitioner may not directly challenge any of the
established RfDs or the established estimate of carcinogenic
potency through a petition demonstration. If the petitioner
has toxicological data suggesting that an RfD or the estimate
of carcinogenic potency be revised, the supporting evidence
may be submitted for review and possible incorporation into
Agency-wide health criteria.
The Agency is considering the idea of taking the severity of
health effects into account in the petition process. However,
the Agency presently is unaware of any practical measure that
would allow the severity Of health effects to be readily used as
a factor in a risk management decision. The Agency might consider
situations where the health effect is minor, completely reversible,
and the exposure causing such a health effect is infrequent.
The Agency is also considering the idea of taking population
size into account in the petition process for non-threshold
constituents. Exactly how the Agency will incorporate population
size to determine a level of risk that is reasonable for a given
-------
30
site and non-threshold constituent has not been fully developed.
In general, the Agency will consider allowing higher levels of
individual risk in smaller populations than in larger ones, as
long as the incidence of adverse effects is the insignificant.
A. Exposure Assessment
Before any assessment of human health risk can be incorporated
into the petition demonstration, it is essential for the petitioner
to thoroughly establish:
1) The relevant toxicologic properties of the waste;
2) The amount of waste to be disposed;
«
3) The concentration of the waste constituents in the
leachate;
4) The long term site specific fate and transport of the
waste constituents.
This information is requisite to establishing possible exposure
pathways and the rate and magnitude of exposure. Only after the
exposure pathways have been established and the likely degree of
exposure is determined can the final steps of risk assessment be
undertaken or can risk management decisions be made.
The petitioner will be responsible for identifying all
potential pathways of exposure over the time the waste remains
hazardous. In addition the petitioner will be responsible for
estimating potential rates of exposure for each pathway for
the length of time the waste remains hazardous. It is important
to understand that exposure scenarios, (iee., pathways and
rates of exposure) are likely to change over time with major
differences occurring when the unit is operating compared to
the post closure period or beyond. Thus, it is incumbent upon
-------
31
the petitioner to anticipate all likely exposure scenarios that
may occur during the time the waste remains hazardous, to
insure that the demonstration is inclusive of all relevant
exposures through time.
The exposure assessment must be based, at a minimum, on the
following types of exposure pathways:
1. Drinking water exposure from either a ground water or
a surface water source;
2. Ingestion of contaminated food (e.g., aquatic organisms
or agricultural products);
*
3. Dermal contact (e.g. recreational use of surface waters,
or bathing);
4. Inhalation of volatile organics, or particulates;
5. Any combination of the above pathways.
For direct pathways of exposure the point of exposure will
be assumed to be at the limits of the area of effective control
which may be the facility waste management boundary unless use
restrictions discussed in Section IV have or will be implemented.
For indirect pathways of exposure, the rate of exposure for each
intermediate point must be estimated. For example, ingestion
of fish by humans will require estimations of constituent
concentrations in the surface water, and account for possible
bioconcentration of the constituent in the food chain such
that a realistic estimate of exposure can be determined for
humans consuming the fish. Taking into account bioconcen-
tration phenomena in the food chain is especially important
-------
32
as it may result in indirect exposures several orders of
magnitude greater than direct exposure pathways. For indirect
exposure pathways that include foodstuffs as the final exposure
medium for humans, the petitioner should determine the frequency
and magnitude of consumption of the foodstuff(s) in the
potentially exposed population. If the petitioner can show
that consumption of any contaminated foodstuff is infrequent
enough such that the magnitude of exposure is minimal, a detailed
analysis of the intermediate points for an indirect exposure may
be omitted. «
The screening level models include an assumption that
half of the RFD will be accounted for from background levels.
The petitioner who challenges the validity of this assumption
for his or her site and waste will be.required to determine
background levels of the constituents(s) at all potential
points of exposure. If a petitioner can demonstrate that
there is no existing background level of the subject consti-
tuent, he or she may use up to 100 percent of the RfD to determine
a site specific screening .level. Background exposure measurements
will be subject to strict quality assurance and quality control
procedures that must be approved by the Agency in advance of
the petition submission. ' Background exposure measurements will
require that both ambient and occupational exposures are taken
into account.
-------
33
The 50% apportionment assumption used in the screening
level models does not apply to carcinogens. Thus the full RSD
corresponding to a 10~6 individual lifetime risk is applied
in the model calculations. In situations where the petitioner
wishes to obtain a variance for land disposal of a waste with a
leachate concentration in excess of the screening level corresponding
to a 10~6 lifetime risk, the Agency may require that the petitioner
determine background levels of the constituent and take into
consideration the prevalance and concentration of other carcinogens
in the potentially exposed population when exposure is ambient
and/or there is a significant occupational exposure in the
population.
In situations where a waste stream contains more than one
carcinogen, an additive approach to the risk assessment estimation
will be taken. The Agency is unaware of any practical methodology
for accurately taking into account synergistic or antagonistic
combinations of constituents. The petitioner should refer to
the EPA publication Proposed Guidelines for the Health Risk Assess-
ment of Chemical Mixtures and Request for Comments? Notice £Part
'III, Vol 50 No. 9 Pages 1169-11767 for a further discussion of
Agency policy regarding estimating risk from chemical mixtures.
B. Population Characterizations
The Agency will require a characterization of the current
or future population likely to be exposed to constituents
leaking from a land disposal unit. The extent of population
characterization will depend on the number of Appendix VIII
constituents in a waste and their toxicological effects,
leachate concentrations, exposure pathways and the relative
-------
34
contribution of each constituent to overall exposure. At a
minimum/ the following population characteristics should be
determined for existing potentially exposed populations:
1) Sex and age distributions
2) Historical growth rates
3) Sensitive subgroups
4) Major occupational categories of existing populations
and type and extent of local industry.
Most of this information can be obtained through the Bureau of
Census, U.S. Department of Commerce,, However, the petitioner
should seek consultation with public health professionals who
*
are experienced with environmental health matters for developing
adequate population characterization data.
The presence of sensitive groups such as (but not limited
to) pregnant women, children, or chronically ill individuals
within a potentially exposed population will affect how r.he
i
Agency will make a risk management decision for a given site-
|
and waste-specific scenario. The petitioner will be required
to identify the size of the most sensitive subgroups within the
potentially exposed population. This subgroup should form the
basis for determining a site-specific risk level and should be /
considered in situations where the generic RfD may be exceeded.
If the petitioner can show an absence of sensitive subgroups
.
for as long as the waste remains hazardous, the Agency may
allow a relaxation of the uncertainty factor (concerning
population sensitivity only) for the RfD of a threshold
constituent by allowing a commensurate exceedance of the RfD.
-------
35
The U.S. Department of Health and Human Services, National
Center for Health Statistics may be a good source of information
on sensitive individuals in the region., All of this information
•should be presented in tabular form to facilitate easy reference.
The presence or absence of sensitive subgroups over the
time a non-threshold constituent remains hazardous will influence
the level of risk that will be acceptable. For example, a con-
stituent that is a teratogen will influence the Agency's risk
management decision depending on the prevalence of pregnant women
in the potentially exposed population.
Certain assumptions are usually made when estimating exposures
from chemical wastes. Although dose rates are the ideal measure
of exposure, the types of data necessary (absorption and excretion
data) for calculating doses for individual constituents are rela-
tively rare and are usually intake route specific. The next best
estimation of exposure is to calculate rates of intake for each
constituent in each media. Standard assumptions used to calculate
intake rates are shown in Exhibit V-l.
Intake rates are a function of the estimated concentration
of a constituent in a medium (air, water, food) at the point of
exposure, the volume or mass of the contaminated medium taken
in by an individual, and the weight of the individual. Human
exposure is expressed in terms of intake, which is the
amount of a substance taken into the body per unit of body
weight per unit time. Intakes are calculated separately for
each exposure medium. In addition, intakes have to be summed
for each medium across all media specific exposure pathways.
-------
36
EXHIBIT
STANDARD VALUES USED IN DAILY INTAKE CALCULATIONS
Parameter
Average body weight, adult
Average body weight, child
Amount of water ingested
daily, adult •
Amount of water ingested
daily, child
Amount of air breathed \
daily, adult
Amount of air breathed
daily, child
Amount of fish consumed
daily, adult
Standard Value
70 leg
10 kg
2 liters
1 liter
20 m3
5 m*
6.5 g
Reference
EPA, 1980
ICRP', 1975
NAS, 1977
NAS, 1977
EPA, 1980
FDA, 1970
EPA, 1980
Example 1; hew to apply the standard assumptions.
If contaminant concentration is 3 rag/liter in drinking water:
3 mg/liter x 2 liters/day water consumption - 70 kg body weight
* 0.086 ing/kg/day intake
Exanple 2; how to apply adjusted assumptions.
If site data indicated that the exposed population has a water consumption
rate of Ii2 liters/day and an average weight of 60 kg, and the contaminant
concentration is 3 rag/liter in drinking water:
3 mg/liter x'1.2 liters/day water consumption - 60 kg body weight
= 0.06 mg/kg/day intake
"S
-------
37
The final result should indicate the total oral and inhalation
exposure to a constituent. Dermal exposures may also be impor-
tant depending on the waste and characteristics of the site.
The Agency will require that the petitioner either document
that dermal' exposure is inconsequential to human health or
estimate the rate of exposure based on the site and waste-
specific scenario. .
The standard values used in daily intake calculations
shown in Exhibit V-l are average values and may not be entirely
appropriate for a specific site and potentially exposed popula-
« - •
tion. There are many characteristics about a population that
may cause sharp deviations from these average values. This is
especially true when exposure occurs via ingestion of foodstuffs
and.liquids. Dietary preferences, methods of preparation, and
age of the individual are examples of factors that can strongly
influence actual intake rates.
The Agency will supply the petitioner with what it
considers to be reasonable assumptions, and/or actual data specific
to a constituent, such that exposure estimates can be made.
The petitioner may wish to develop data concerning human intake
routes instead of using assumptions. The acceptability of any
data of this type developed by a petitioner will require strict
adherence to a QA/QC plan approved by the Agency. The application
of this data for exposure estimates most be carried out by a
qualified toxicologist or similar health professionals.
-------
38
A major .emphasis of the petition demonstration rests on the
estimation of long term (chronic) exposures to relatively low
concentrations of constituents. This type of exposure estimation
leads to calculation of a chronic daily intake (GDI) to char-
acterize the risk from non-catastrophic failure of a land dis-
posal unit. However, there may be site and waste specific
scenarios where there is a significant probability of catastrophic
failure. In situations where catastrophic failure has a
significant probability, the Agency may require that a
petitioner estimate a Subchronic daily intake (SDI) to assess
the risk in such a scenario. The major difference in determining
an SDI versus a GDI will be in the prediction of the fate and
•transport of a constituent under the specific catastrophic
conditions.
C. Risk Management Factors
The greater the degree of certainty in the quantification
of potential exposure for a population the greater the level of
confidence there will be in the entire risk assessment process.
Greater certainty will allow a higher level of confidence in
'making risk'management decisions, for a specific site and waste
scenario.
-------
39
The Agency will place considerable weight on the sources
of uncertainty in the petition demonstration. The major sources
of uncertainty come from the:
1) fate and transport analysis
t
2) toxicological data
3) risk estimating procedures.
For non-threshold toxicants, risk management decisions
are an inherent part of the process to establish a level that
is protective of human health. The petitioner should refer to
the November, 1984, EP£ Proposed Guidelines for Carcinogenic
Risk Assessment (FR46294) to gain insight into Agency protocol
for estimating human health risk due to nonthreshold toxicants.
The Agency believes that the establishment of a single across-
the-board risk level for carcinogens is not appropriate since
no dose level is "safe" under all circumstances and since
carcinogens differ in the weight of evidence supporting the
hazard assessment. The cited guidelines explain how the Agency
will handle differences in the weight of evidence that a compound
.is carcinogenic. Where the weight of evidence suggests that a
compound is a known or probable human carcinogen, the protective
dose would be calculated for the 10~6 level. The 10~6 level
is viewed by the Agency as a point of departure for making
risk management decisions. Choice of 10~6 as the initial
risk level of concern is made on the basis of past Agency
decisions. In general the Agency has made decisions to allow
-------
40
concentrations of non-threshold toxicants where the individual
risk values have been within the range of 10""* to id~70 The
range of allowable risk -will b® integrated with the weight of
evidence approach and the nature and size of existing or future
potentially' exposed populations. In other words the Agency
will tend to favor conservative risk levels where the weight
of positive evidence is strong? and there is a large potentially
exposed population, and b© less conservative where.the weight
of positive evidence is less and the potentially exposed population
is saall. The weight of evidence approach, however, requires
4 [
that there is adequate data to evaluate a compound for carcinogenic
potential. A lack of data will cause the Agency to take a
conservative approach to the risk management process, since the
I •
Agency will not be able to assure that the coiapound is non~
carcinogenic. ,
For threshold toxicants, out of necessity, risk management
decisions have a narrower scope. The RfDs for threshold
toxicants are. determined primarily from animal toxieologieal
studies which are designed to make point estimates of health
effect levels« A priori, the level of risk is set in the same
way regardless, of the constituent. That is, the RfD is set at
a level where no observable adverse effects occur. Because
i
the RfD is based on chronic lifetime exposure to a specific
daily amount of a. substance, it may not always provide a
reasonable guide to evaluating the risks of possible exposure
scenarios. This will be especially true of episodic exposures
-------
41
at relatively high doses. If the petition demonstration can
establish such a scenario, it must, also be supported by
toxicological data that realistically reflects the exposure
conditions..
Another scenario that may allow approval of a petition
would be when the petitioner is able to demonstrate with great
certainty that the maximum rate of exposure will only slightly
exceed the RfD. In this case, a qualified toxicologist might
judge the amount exceeded to be negligible compared to the
statistical error of the toxicological data.
VI. 3rd Tier Analysis - Elements of a Detailed Site Analysis
A. Objectives
For those petitioners that either choose to perform a
detailed site analysis, or are ineligible for a 2nd Tier
Analysis, the following is a brief description of the
components that may be necessary, and an explanation of the
quality and quantity of the appropriate data and analyses. Any
petitioner performing a 3rd Tier analysis enhances the chances
for approval by providing the most accurate and precise information
possible. Accuracy and precision are evaluated by the degree
to which quality control procedures are followed. The preparation
of a thorough, comprehensive quality control plan is, therefore,
-------
42
an integral part of any 3rd Tier analysis. Quality control
procedures apply to-any data collection and data analysis,
including the use of computer simulation models for analyzing
potential migration in the air/ soil, surface water/ and ground
water.
B. Petitioner Conference
It is.recommended strongly that the petitioner request a
conference with the Agency petition reviewer prior to embarking
on extensive petition preparation. The petitioner should be
prepared to discuss in qualitative terms the unique features of
the disposal unit that may justify granting a petition/ and the
type and degree of analysis that the petitioner feels is
necessary to make an adequate demonstration. It will probably
not be necessary to include extensive analyses in all of the
cases discussed below to satisfy thefrequirements of a 3rd Tier
analysis. If the petitioner has performed a 2nd Tier analysis,
it may be obvious that a certain physical site feature (e.g./
the unsaturated zone/ the topography/ etc.) requires the most
in-depth site analysis. The purpose of the conference will be
to agree upon the nature and extent of the analysis required/
and to discuss/ in general/ the criteria that the Agency will
use to evaluate the data/ analyses/ and quality control procedures
of the petitioner.
-------
43
The following example illustrates the type of situation in
which a petitioner conference would be useful and the type of
discussion that would be appropriate. The petitioner is ineligible
for a 2nd Tier Analysis since the disposal unit is located in
close proximity to an active fault (Screening Factor. II-1)..
The petitioner believes that any seismic activity that is
likely to occur would have- little or no affect on the integrity
of the disposal unit during its operating period or following
closure. To demonstrate this, the following considerations
would be required: I .
1. The magnitude of likely ground motion at the disposal
Unit site?
2. The magnitude and type of likely surface displacement
within 1 km of the site;
3. The potential for seismically induced ground failure?
4. The potential for damage due to tsunamis in areas of
the country known to be vulnerable.
Ground motion at a site is partly a function of the dis-
tance from the epicenter of a fault, the thickness and areal
extent of surficial deposits, the lithology and degree of
consolidation of these deposits, and the nature of the disposal
unit itself. A geotechnical investigation and analysis o,f the
site may be undertaken to show that the disposal unit will
withstand the maximum likely ground motion for the site, or a
simplified analysis may be undertaken based on the assumption
-------
44
of complete failure of the disposal unit. The first approach
would have to show that catastrophic failure would not occur
while the second approach would have to show that in the event
of catastrophic failure, the natural site features would still t
contain the hazardous constituents such that human health and
the environment are protected.
The Agency will deny any petition where the disposal unit
is sited within a fault zone where surface displacement has
occurred'in the past 10,000 years iHolocene). In a seismically
active zone the petitioner will be required to establish that
ft i
evidence of Holocene surface displacement is not any less than
"1 km from the site boundaries. Evidence of Holocene displacement
must be established by using available data from the U.S. or
State Geological Surveys, published maps and reports. The
petitioner will also be advised to obtain the services of a
qualified registered geologist to perform a geologic recon-
naissance of the area within 1 km of the site. The geologist
report must also include a discussion on how any changes in
the natural -drainage due to displacement might affect a site,
if there is evidence of Holocene surface displacement.
In seismically. active zones the petitioner may be required
to assess the potential impact of seismically induced ground
failure. A geotechnical investigation and analysis should be
designed to estimate the likelihood of ground failures caused
by liquefaction which might result in lateral spread of large
blocks of soil, flow failures, or loss of bearing strength.
-------
45
If. a site is located on or-adjacent., to. moderate to steep slopes,
the potential for landslides must be assessed. The investigation'
must show that either ground failure will not occur, or, assuming
worst case conditions, that a catastrophic; failure will not en-
danger human health or the environment.
The historical record for tsunamis wilX provide the petitioner
whose site is located in a coastal setting an indication of the
vulnerability of the site* The petitioner must show that the
site is out of reach of a tsunami because of topagraphic barriers
or height, or that the disposal unit is designed to withstand
* • ,. . .
the impact of a tsunami. A petitioner whose site is located
in a seismically active area and is adjacent to a lake will have
to make a demonstration similar to that for a tsunami. The
petitioner and: the petition reviewer will agree upon the extent
of the investigation that is reasonable for the actual con-
ditions of the subject disposal unit.
C. Components
Following; are brief descriptions of the possible components
of a 3rd Tierr analysis. Various appendices provide more detail
on the data and analyses/ and; provide references to source
material and. Agency guidance dbcumentsv The contents of the
petition should include but not necessarily, be limited to the
following topics which are more fully discussed in separate
sections in this manual.
-------
46
1. Synopsis (including checklist). The synopsis is the
first section in the petition and should be in the
form of an executive summary. It should include
facility identification, discussions of the contents of
the petition and the conclusions drawn from the
analyses. It should also include a directory (in the
form of checklists) to guide the petition reviewer in
locating specific elements. The synopsis should include
j
a discussion of any deviations from the recommended
format. (See discussion below.)
• • ,
2. Facility Description. In this section the facility
'should be characterized by physical description,
natural setting, design, construction, and operation.
Also, there should be site plans, closure and post-closure
I
care plans and QA/QC for design, construction and operation
of the facility included, where appropriate
3. Waste Characterization. This section should include
the completed forms shown in Section II and appropriate
discussion of the waste(s) and its hazardous constituents.
4. Waste Interactions and Effects. This section should
discuss the changes in waste characteristics, both
physical and chemical, that may occur as a result of
waste interactions within the unit. Four major categories
of interaction are described in this manual which gives
specific guidance in writing this section.
-------
47
5. Waste Mobility in the Unsaturated Zone. Using
information on site;characteristics, waste characteristics
and waste interactions, this part of the petition should
discuss the probable movement of the waste constituents
through the soil zone, intermediate unsaturated zone,.
and the capillary fringe. It should include a complete
discussionof themodel(s) used and describe the QA/QC
procedures used.
6. Waste Mobility in the Saturated Zonetv This section-
should describe the probable movement of- the hazardous
constituents of the wastes' within the saturated, zone.
If the waste remains hazardous during its passage
through the unsaturated zone/ this section should
demonstrate that the waste: will not migrate beyond the
area of ef f ect ivei control in a- hazardous form via the
saturated zone. It;should include 'a complete discussion
of! the model(si used and describe the QA/QG procedures
used.
7, Waste Mobility in Surface Waters. Thiss section should
demonstrate that hazardous constituents of the waste will
not migrate beyond the area of effective control in-
dissolved' or suspended form in surface waters^ It-
should include a complete discussion of the model(s)
used and describe the QA/QG procedures used.
-------
48
8. Waste Mobility in the Air. This section should
demonstrate that hazardous constituents of the waste
will not migrate beyond the area of effective control
through the air. It should include a complete discussion
of the models used and describe the QA/QC procedures
used.
9. Human Health Risk Assessment. Using data presented in
the previous sections and other information as
appropriate, this section should present an assessment
of potential.risks to human health arising from the
land disposal of the subject waste. This should
include risks to facility personnel as well as the
human population at large. Probable exposure pathways
for hazardous constituents should be developed and
then the effects of exposure .estimated. Section V
provides more specific guidance on this topic.
10. Potential Damage to Wildlife and Vegetation. Information
from previous sections should be used to evaluate probable
pathways by which wildlife and plant populations could
be exposed to the hazardous constituents of the waste
and also the effects of exposure on the fauna and flora
should exposure occur. Both terrestrial and aquatic/marine
communities should be included in the assessment.
-------
49
11. Documentation. Data, modeling results, procedures, and
associated QA/QC for facility design, construction and
operation should be documented in one or more appendices
as needed. Reference to the various appendices should
be made in the text of the petition, as appropriate.
D. Model Validation
The petitioner is responsible for performing adequate
validation of the use of any models other than the unmodified
versions of the Screening/Treatment Level models. Validation
may involve comparison of various analytical model results to
the results of the models used in the petition, or it may involve
history matching of field data collected over a certain period
of time with detailed modeling of the same time period, assuming
the initial and boundary conditions existing at the field site.
The petitioner should include sufficient information to
demonstrate the accuracy of the model results for the particular
application. The goals of this demonstration may be summarized
as follows:
a. the model reasonably represents the actual physical
system; and
b. There are no computational errors in the computer
code.
To achieve these goals, the petitioner should address each
of the following areas:
-------
50
1. Identification, of objectives of the modeling study;
2. Description of the conceptual approach;
3. Description of the solution methodology employed to
predict contaminant migration; and
4. Description of the rationale for the selection of input
parameters.
The petitioner should present adequate information addressing each
•
of the above, consistent with the type and level of modeling con-
templated.
If the petition demonstration involves the use of an analytical
groundwater flow model, for example, the petitioner should verify
the model results* by comparison to other analytical flow models,
and by comparison to solutions presented in the original references.
A numerical groundwater flow and transport model may involve more
detailed verification, such as the following steps:
1. 'Identification of the capabilities, assumptions, and
limitations of the numerical code;
i
2. Justification of the grid and time increments through
description of the geometry and flow characteristics
of the site;
3. Justification of the compatibility of each code, when
two or more codes are used to solve the flow and trans-
port problems.
4. Demonstration of a high degree of predictive correlation
between the model results and actual measured data.
-------
51
The Agency is aware of a variety of models that simulate the
fate and transport of hazardous constituents in the air, in
surface water/ and in ground-water. Available models coyer the
range from very simple to very sophisticated, from requiring a
few, slapIs parameters to requiring large volumes of specific
data, from very general results with large uncertainty to very
specific results with less uncertainty. The petitioner will be
responsible for selecting the most appropriate modeling approach
for the situation to be .simulated. If the problem at hand calls
for an analytical groand-water flow model, the petitioner may
select such a model from the many that are available or develop
a new model that is suitable to the situation. If a more complex
problem is to be analyzed* a more sophisticated model, capable
of managing large volumes of site-specific data, may be more
appropriate. Where interactions or inter-media transfers occur,
such as at the soil-air interface, or where ground water discharges
to surface water, a combination of models may be integrated.
The Agency will accept any type of simulation model, or combinations
of models, for the purpose of predicting the ultimate face of
hazardous constituents of the subject waste, as long as the
overall modeling approach can be technically supported as being
most appropriate to the waste and site conditions and most capable
of producing accurate and reliable results.
The Agency will use the following general criteria in
determing if a proposed modeling approach is appropriate and
will produce results with the desired quality. First, the model
-------
52
must be compatible with the quality and type of input data
available. Second, the model must have been demonstrated to be
applicable to the environmental conditions at the site of the
subject disposal unit. Third, the computer code must have been
subjected to an independent quality assurance audit, or have
been subjected to a level of professional peer review equivalent
to that for publication in a scientific or technical journal.
Fourth, the approach must be internally consistent in the use of
boundary and initial conditions, time stepsm assumptions, and
code modifications. Fifth, fully documented support for the
modeling approach selected by the petitioner must be available
to the Agency.
E. Format
The petitioner should present each of the items listed
above as a section of the petition. Each section should be as
self-contained as possible. They should include all data,
figures, drawings, etc., needed to support the specific aspect
of the petition being addressed. If necessary, separate binders
for some sections may be advisable. 1
•
The synopsis should contain complete identification of the
facility for which a variance is being requested.. This should
include all the information required on EPA Form 3510-1, the
general information portion of a RCRA Part A permit application.
A copy of Form 3510-1 may be included in the synopsis.
-------
53
Conclusions that have been drawn from the petition infor-
mation should be included in the synopsis and they should be
briefly explained in relation to the performance standard. If
conclusions are drawn based on rationale,, data, or models that
are different from the guidance explained in this document,
such deviations should be briefly explained in the synopsis.
Detailed discussions and explanations should be confined to the
appropriate sections of the petition.
The synopsis should be general in nature as compared to
the other sections of'the petition. The other sections address
specific technical areas. Each area presented should be
presented in .a self-contained section. Each should contain the
information, data, maps, calculations, logs, etc. to fulfill
the petition requirements for a specific feature of the proposed
waste disposal facility. The synopsis should refer to the self-
contained sections such that the petition reviewer can easily
relate the synopsis to the sections.
The self-contained sections will greatly aid the evaluation
and review of petitions, as well as any subsequent writing and
•issuance of variances. Reviewers and variance writers will, in
turn, assess these sections and incorporate them into the
variance. Sections acceptable to EPA as proposed by the peti-
tioner, may be incorporated without change into the variance.
-------
54
If during review, additional information is required? EPA will
identify such information or return the appropriate sections
to the petitioner for revisions rather than return the entire
petition* • The resulting variance may contain the sections
prepared by the petitioner, either as originally written or as
r
modified by EPA or the State.
Sections should be clearly identified with either a letter
or number and appropriate title. Sections should have page
numbers, figure numbers, etc., that relate to the section
*
identifier letter or number. Sufficient petitioner and facil-
ity information should be provided on the first page of each
section to uniquely identify the petition of which it is a part.
The use of color-coded pages should be given consideration
for confidential business information (CBI). CBI should be
identified clearly as was done in the related RCRA Part B permit
application.
The use of figures, tables, and other illustrative tech-
niques are encouraged where their use would aid the evaluation,
review, and variance writing. The use of color graphics should
also be considered'in this regard.
Petitions should contain tables of content for the overall
petition, as well as each section. The inclusion of such items
as indices and cross references should be considered in the
development of the petition.
-------
55
All portions should be legible and reproducible. Appro-
priate margins and spacings will ease evaluation and review of
the petition. Maps, plans, etc., should be provided at an
appropriate scale. Each page should contain a date of original
issuance or date of revision on the upper right corner.
E. Technical Assistance
In the preparation of a petition, most petitioners will
likely require technical assistance f.rom specialists, including
but not limited tos engineers, geologists, hydr©geologists,
and soil scientists,, iThese specialists may be part of the
petitioner's staff or outside consultants. The EPA feels that
petitioners will obtain the best service (designs, plans, etc.)
and thus the most complete petition, if they use only fully qual-
ified technical expertise. Particularly important is experience
in hazardous waste management closely related to the proposed
facility and wastes.
The use of registered, professional engineers in the
preparation of a variance petition is encouraged* Part 264
requires certification by a registered, professional engineer
that a facility has been closed in accordance with an approved
closure plan. Engineers are registered by all 50 States.
Registration is based on combinations of education, experience,
and examinations. Registration licenses engineeers to practice
their profession, and includes legal and ethical restrictions
regarding the technical extent to which services may be offered.
Registered engineers may not practice beyond their areas of
-------
56
expertise. Additionally, registered engineers are required by
law to place public health, safety, and welfare before other
aspects of their assignments.
The petitioner should .obtain the best assistance possible
in the preparation of a petition. EPA recommends that engineers
experienced in hazardous waste management be involved with
preparation of petitions. Also, it highly recommends that
registered, professional engineers (registered in the State in
which the facility is located) be utilized in the development
of necessary designs,*specifications, certifications, etc. The
combination of applicable experience and registration on behalf
• : ,
• i «
of engineers involved should result in a petition (and resultant
facility) that meets the technical requirements and spirit of
the regulations. Proper qualifications are most important;
however, professional registration is also considered an important
credential. If the regulations require a registered engineer,
even the best qualified, non-registered engineer will not meet
the requirements.
Aga'in, experience in land-based hazardous waste management
is the most important credential for geologists, hydrogeologists,
and soil scientists. Some States and professional organizations
register geologists and hydrogeologists in a manner similar to
engineers. It is recommended that experienced, registered
professionals be involved with the petition.
-------
57
In lieu of registration, several national organizations
certify geologists, hydrogeologists, and soil scientists.
Certification generally indicates- that an individual has; the
basic educational requirement and (usually) experience? to be
considered a member of that profession.
Whenever an exposure and population: analysis is included in
a petition demonstration, the services of' a*, qualified: toxicologist?
or public health professional is desirable* These professionals
should be familiar with the Agency'%; policies for; developing
health effects criteria and should have had experience in conducting
a human health risk assessment for environmental exposure scenarios.
F. Related Guidance^ Documents
The EPA has published several guidance documents related
to the submittal of RCRA Part B permit applications and to the
performance of: risk assessments:. These documents address prepa-
ration of the applications and technical aspects related to the
design and operation of land-based hazardous waste facilities.
These documents may be helpful in the preparation of a variance
petition. A liat of selected documents: follows.
Publications with source shown as NTIS can be ordered; from
the National Technical Information Services; in Springfield>
Virginia, at (703) 487-4650. Publications from; the Government
Printing Office (GPO) may be ordered by calling (202) 783-3238.
Stock numbers are; shown for GPO publications and publication
numbers are shown for those from NTIS.
-------
58
Title
i
Permit Applicant's Guidance Manual for
Hazardous Waste Land Treatment, Storage,
and Disposal Facilities (530 SW-84-004)
Evaluating Cover Systems for Solid
and Hazardous Waste (SW-867)
Hydrologic Simulation Waste Disposal
Sites (SW-863)
Landfill and Surface Impoundments
Performance Evaluation (SW-870) '
Lining of Waste Impoundment and
Disposal Facilities (SW-870)
Management of Hazardous Waste
Leachate (SW-871)
Guide to the Disposal of Chemically
Stabilized and Solidified Waste (SW-872)
Closure of Hazardous Waste Surface
Impoundments (SW-873)
Hazardous Waste Land Treatment (SW-874)
i
Test Methods for Evaluating Solid
Wastes (SW-846)
A Method for Determining the
Compatibility of Hazardous Wastes
(EPA-600/2-80-076)
Soil Properties, Classification,
and Hydraulic Conductivity Testing,
Draft Technical Resource Document
(SW-925; 1984)
Solid Waste Leaching Procedure,
Draft Technical Resource Document
(SW-924; 1984) '
Procedures for Modeling Flow
Through Clay Liners, Draft Document
(EPA/530-SW-84-001; April 1, 1984)
Source
GPO (055-00-00240-1)
GPO (055^00-00228-2)
GPO (055-00-00225-8)
GPO (055-00-00233-9)
GPO (055-00-00231-2)
GPO (055-00-00224-0)
GPO (055-000-00226-6)
GPO (055-000-00227-4)
GPO (055-000-00232-1)
GPO (055-002-81001-2)
NTIS (PB80-221005)
RCRA Hotline
(800) 424-9346
RCRA Hotline
(800) 424-9346
RCRA Hotline
(800) 424-9346
-------
59
Title Source
Superfund Public Health Evaluation U.S. EPA Office
Manual - Of solid Waste
and Emergency
Response
Superfund Exposure Assessment Manual U.S. EPA Office
of Solid Waste
and Emergency
Response
Background Document for the Ground-Water U.S. EPA, Office
Screening Procedure to Support the 40 CPU of Solid Waste
Part 268 Land Disposal Restrictions
Background Document on the Development U.S. EPA, Office
and Use of Reference Doses to Support of Solid Waste
40 CFR Part 268 Land Disposal Restrictions
Background Document for the Surface U.S. EPA, Office
Water Screening Procedure to Support of Solid Waste
40 CFR Part 268 Land Disposal Restrictions
-------
60
V. Summary of the Conditions of an Approved Petition
For every petition that the Agency or authorized state
approves/ certain minimum conditions regarding the subject waste,
the disposal unit, and relevant management practices will be
specified. Additionally, certain specific conditions that
identify grounds for revocation of the approved petition and
possible enforement action will alsb be specified. Although all
i '
of these conditions will be very dependent on the individual
petition, there are certain general components that would be
included in every approved petition. These components are
briefly described in the following paragraphs.
'Each approved petition will contain precise descriptions
of the subject waste, in chemical and physical characteristics,
the concentration of hazardous constituents and the range of
variables of these concentrations, and the volume or .weight
of the waste to be managed in the subject disposal unit. The
petition will also contain a complete description of the disposal
unit, in terms of physical location and dimensions, and current
ownership. The petition will specify the length of time over
which the approval is effective and will state exact dates by
which a renewal or re-application is required. This latter
information-will be dependent upon the status of the operating
permit of the disposal unit at the time of petition approval.
In addition, if any petition is approved on a conditional basis,
(e.g., conditional on the basis of additional monitoring results,
or the results of some long-term analyses) the details of the
condition and the petitioner's responsibilities would be
specified.
-------
Under certain circumstances, an approved petition may be
revoked^ and possible enforcement action, to include fines and
imprisonment, may be necessary. In general, such circumstances
would include significant changes in the subject waste or in the
site characteristics that could not have been foreseen at the
time that the petition was approved, or the subsequent obtaining
or developmentof relevant information that was not available
to the petitioner or the Agency at the time the petition was
approved. Additionally, if the petitioner fails to obtain the
required operating permits, or is not in compliance with current
permit requirements, the Agency may decide to commence enforce-
ment action, and this may result in petition revocation. In
the case of a significant changes in the physical characteristics
of a waste that are either to process changes that involve
different raw materials or to mixture of the waste with other
materials, the. generator of the waste or the person who is
knowledgeable of these changes is responsible for reporting the
change in waste characteristics to the Agency or to the state
that had approved the petition.
-------
-------
APPENDIX I
SCREENING FACTORS
-------
-------
1-1
APPENDIX I
I. Approval and Rejection Criteria
A. Approval Criterion
A petition for removing restrictions ton the land
disposal of a previously restricted hazardous waste is
^approved for a specific disposal ariit if the disposal ;unit
owner or .operator can demonstrate that no exposure to
humans or to environmental species tar systems will occur
through- any pathway "for as :iong «s the wastes remain
hazardous. *
B. Rejection Criteria
A :pe.tition for removing restrictions on the land
disposal of a previously restricted hazardous waste is
reiecte:d for a specific disposal unit if*
"1-. The petitioner fails to submit an analysis
documenting the validity of any ^fate and transport
model, other than the unmodified version of the
Screening/ Treatmefnt Standard models, to be used
in evaluating the ^disposal ;urcit site.
:2. The petitioner fails to JSuJbmit for Agency approval
a comprehensive quality assurance/quality control
plan for all sampling ;and ^analytical techniques to
toe used in tievelop:ing the petition demonstration.
3. The owner or operator of the disposal unit has not
provided to the Agency or State all relevant Bart B
information, including all relevant Part 270.14(c)
information.
-------
1-2
II. Approval for Performing a 2nd Tier Simplified Analysis
Approval is granted for performing a 2nd Tier Simplified Site
Analysis for a petition for removing restrictions on the land
disposal of a previously restricted hazardous waste ifs
1. The disposal unit is not located within 1 Km
of a fault which has had displacement in
Holocene time.
2. The disposal unit is not located in a 100-year
floodplain, unless granted a variance as re-
quired under Part 264»18(b).
3. The disposal unit is located at a site where
the inherent geologic,, hydrologic, and pedo-
logic features can be adequately characterized,
to ensure that all significant ground water flow
paths can be monitored.
4. The disposal unit is not located at a site in
close proximity to kairst topography, subsurface
fractures and bedding planes, active volcanic
impact zones, landslide-susceptible areas, sub-
sidence-prone areas, or weak or unstable soils.
5. The disposal unit is not located at a site where
ground water withdrawal, natural infiltration, or
any type of subsurface injection significantly
affects the ground-water flow systems to the
extent that the integrity of the disposal unit
is threatened by contact with the ground water.
-------
1-3
6. The owner or operator of the disposal unit is ,
not required to perform compliance monitoring under
Subpart p unless an ACL has been granted, or is not
performing corrective action.
-------
-------
APPENDIX II
PROPOSED LAND DISPOSAL
RESTRICTIONS
-------
-------
II-l
Fedatri Begbteg / VoL il. No. 9 / Tuesday. faauary 14. 198S / Proposed Bate
PART268—LAMD DISPOSAL
RESTRICTIONS
VL fa Part 260. proposed in the
Federal Register of May 31,1885 (SO FR
23255):
1. The authority citation for proposed
Part 268 is revised to read as follows:
Authority: Sees. 1000,2002(a). 30OT. and
3004 of the Solid Waste Disposal Act as
amended by the Rmource Conservation and
Recovery Act of 1978, ai amended by the
Hazardous and Solid Waste Amendmenu of
1984 (42 U.S.C. 6605,6812(a}. 6921. and 6924).
2. By adding Subpart A to proposed
Part 288 to read as follows:
Subpart A—General
SK.
288.1 Purpose scope, and applicability.
2S&2 Definitions applicable to this part
2603 Dilution prohibited as a substitute for
treatment
268.4 Provsdwvf for extensions to on
effective date.
2883 Petitions to allow land disposal of a
waste prohibited under Subpart C of Part
2008 Waste analysis.
268.9 Incorporations by reference.
Psspssa, smf apefeaontv.
(•} This peit ideaJifies hazardous
wastes that a?© restricted from land
diaposal and thsss limited
drcumstanosa wd@g which an
otherwise prohibited waste may
continue to be land disposed.
(b) Except as spedScaDy provided
otherwise w this part or Part 261 of this
chapter, ths requirements of this part ,
apply to pesssrai wh® generate or
treatment, storage, and disposal
facilities.
(c{ Hie resusirsiffiente of Subparts A, C
D and £ of this p@ri da not apply to the
disposal of haaazdos® waste by
(d) The requirements of this part appl
treats, stores, or dfspasea of hazardous
waste in a State which is authorized
under Subpart A or B of Part 271 of thii
chapter if the State has not been
authorized to carry out the reqmremen-
genesatiois. teaspsst, treatment storai
or disposal of femsafdiB«,5§ waste which
are imposed pmraaaat to the Hazardou
and Solid Waste Amendment? of 1984
The requiremeats and prohibitions the
are applicable until a State receives
authorization to carry them out includ
all Federal program requirements
identified in § 271.10} of this chapter.
(e) The requirements of this part do
Hot apply to parsons placmg hazardoi
provided thai:
(1) Treatment of sisdi wastes occur
tfaa
(2) The soGtenta of the impoundme
must be analyzed, through nse of the
test methods described in SW-848 ai
the residues of snch treatment (indu
any liquid waste) that do not meet tf
treatment standards promulgated on
Subpart O of this part or are not
delisted under 1 260.22 of this chepti
must be removed at least annually e
may not be placed in a surface
impoundment for subsequent treatzc
The procedures and schedule for (i)
sampling of impstimdment contents^
the analysis of test data, sad (in] th
annual removal of iresidus which dc
not meet Sdbpart O treatmsat stanc
must b@ e{9@ci53d is the facility's w
analysis ptea as faqtdred under
I § 284.23 ear 28S.23 af this chapter.
(3) The iiBjsffisijKteejaS saests the t
requirements of § 2S4J22J(c) os
§ 2§5-221{e| of tMs chapter, unless:
-------
Fcdtni Register / Vol. 51. No. 9 / Tuesday.
llule
1781
Ixnapttd panaaat to i 284221 {d)
of this chapter, or { 2o%221*(c) or
tkls chapter, or
Upon application of the owner or
tor prior to Novsunber 8.196S, the
alitrator has granted a waiver of
quireswats oa tha basis that th»
aimpotmcteent:
Has at bust on* lln^r. for which
Isoo tntidtmm that such liner is
U located:
i thaa oftt-qosrter
'rca as andcrsrcead towes of
EngwattRaad
la in ccaapltessa with the generally
abb grotad water moiitodzig
rKoesta for facilities with pmraits:
f Upon appJfcasHwi of the owner or
.tor prior to November 8.1888, the
jjisfrater has granted a
Station of th* reqnirsiaeats on the
of « demonstration that the
e* impoandawat is located,
atd, and operated so as to aswira
h«f* will a* no migration of any
•dou* cosstitiMat into grocod water
rf«ca water at any future tim>.
The reqoireoawits of this part do
ppjyte
ftnrseas' wio haw beta granted a
IBC* fitma « prohibitiai ptosoant to
13. with mpsst to thott wastes and
covered by to* variance: or.
any land dicposal of contaminated
» debris revolting &om a response
Q takan tinder section 102 or 103 of
Jomprohanihr* Enviroomsntal
ocae. Compensation, and Liability
of 1980 or « corrective action
irtd end«r Part 28* or SOS of this
iter until Nowmber 8,1B6&
J A genera tor or an owner or
star of a facility otherwise
latsd by this part must comply with
ppUcabla raqtilreni«nts of this
>ter.
12 'DelWtteaaiJpaeiMatotWsptst.
) When usxd in this part the
rwing terms have the meanings given
w:
\rea of effective control" means an
t where perpetual restrictions exist
be use of any air or water resources
manner that would-not be
ectlve of human health and the
Jroament If this area extends
ood the waste management area, as
aed at { 28C95(b) of this chapter.
actual restrictions on the use of any
or water resources must be
ibllthed by an act of tha local or
la legislature.
Hazardous coosUtutent or
.stituttts" means thosa constituents
ed to Appeadix VIU to Pert 261 of
»chapter.
"Land disposal" means placement in
or on the land and includes. but is not
limited to, plecfflEsat in a landfill.
surface impoundment waste pile,
tejectioa wall1, land treatment facility.
salt doras fdrmsiioR. f alt bed formation.
undergrooadmirae or cave, concrete
vault or banker intended for disposal
purposes and placement in or on the
land by means of open detonation. Tha
terja "land disposal" does not
encompass oceaa disposal
(b) All other terms have the meanings
given undar §§ 2Sam 281.2. 281,3. or
27O2 of this chapter.
fW traaanant,
No gaasator or owoe? or operator of
a treatment storage, or disposal facility
shall in any way aitesspt to dilute a
waste as a substitute for adequate
tre8tmaat|to aehisv* compliance with
Subpart O of this part.
(e) Any persca who generates, treats.
stores, or disposes of a hazardous waste
restricted (or proposad to be restricted)
from land disposal pursuant to Subpart
C cf this part may submit an application
to tha Adrafaiateator for an extension to
tha ef?eti?fcc data of any applicable
restriction established under SI 28&3Q,
26&31. or 283.40. The applicant must
demomtrats the following:
(1) Ha baa entered into a contract to
construct or otherwise provide
alternative treatment, recovery
(recycling), or disposal capacity that
protects human health and the
environment The contract must contain
a penalty for cancellation that, in the
Agency's judgment is sufficient to
discourage cancellation by the
applicant
(2) Due to circumstances beyond the
applicant's control such alternative
capacity cannot reasonably be made
available by the applicant by the
applicable effective date.
(3) The applicant has made a good-
faith effort to locate and contract with
treatment recovery, or disposal
facilities nationwide to manage his
waste in accordance with §§ 266.30 or
268.31.
(4) The capacity being constructed or
otherwise provided by the applicant will
be sufficient to manage all of the waste
that ia tLe wbjeci of the application.
(5) Tha applicant has prepared and
submitted to the Administrator &
detailed schedule for obtaining required
operating permits and construction or an
outline of how and when alternative
capacity will be provided.
(6) The applicant has arranged for .
adequate capactiy to manage his waste
during an extension and has
documented in tha application the
location of aii sites at which tha waste
will be managed.
(7) Any wants managed in a surface
impoundment or landlm during the
extension period will meet the
requirements of paragraph (i) (2) of this
section
(b) Any parson signing an application
described under paragraph (a) of this
section shall make the following
certifications
I certify umto penalty of law thai! haw«
p«Ke£3% exemted aced em familiar writh
the tofonnstta wubraittad in this document
and ail attachraeats and that, basod on my
inquiry of these Individual* tamediatal;
responsible far obtaining the information, I
besiera thet tha taforaatlca is tme. accurate.
end emnpieta. I am awara that ihsm wea
significant pemaitiea for submitting false
IsjfoHEation, iBeteding th« possibility of fine
8AQ |ESl3f?&J3QS£i43SX8U
(c) On the basis of the information
referred to in paragraph (a) of this
section, after notice and opportunity for
comment and after consultation with
appropriate State agencies in all
affected States, tha Administrator may
grant an extension of up to 1 year from
the effectiva data. The Administrator
may renew this extension for up to 1
additional year upon the request of the
applicant In no event will an extension
extend beyond 43 months from the
applicable statutory effective date
specified in section 3Q04(d], (e). or (g) of
the Act (42 U.S.C 6S24(d}. (e). or (g)).
(d) Tha length of any extension
authorized iu paragraph (c) of this
section will-be determined by the
Administrator based on the time
required to construct or obtain the type
of capacity needed by the applicant as
described ia the completion schedule
discussed in paragraph (ffi)55) of this
section.
(e) The Administrator will provide the
successful applicant with written notice
of the extension. This notice will
describe the manufacturing process that
is the source of the waste subject to the
extension, the. volume of such waste, the
duration of the extension, and the name
and the location of the facility
designated in paragraph (a)(8| of this
section to manage the waste during the
period of the extension. Tha applicant
must retain a copy of the notice during
the period of ths extenakm and for at
least 3 years after the extension expires.
(f) The applicant must provide a copy
of the notice to the facility designated in
. paragraph (a)(6) of this section. The
notice must be provided to the
-------
n-3
1782
/ Vol-SI. No. § / Tuesday. January 14, 198@ / Proposed Rules
designated facility prior to the first
shipment of waste which i* the subfest
of the extension. The owner or opreator
of the facility shall retain a espy of tfea
notice during the period e£ the extension
and for as least 3 years after the
extension expires.
(g) The successful applfegsai must
immediately notify the Administrator as
changes in the s^R^tioros certified to in
the application.
(h) The successful applicant must
submit written progress reports at
Administrator. Such rspsrts must
describe the overall progress mads
toward constructing or otherwise
providing alternative treatment.
identify any event which may cause or
has caused a delay to She development
of the capacity; and must summarize the
steps taken to mitigate the delay. The
Administrator can revoke the extension
at any time if the applicant does not
demonstrate a good-faith effort to meat
the schedule for completion, if the
Agency denies or revokes any required
permit, if conditions certified in the
application Changs, or for any violation
of this part.
(i) Whenemr tha Administrator .
establishes an extension to an effective
date under this section, during the
period for which such extension is in
effect:
(1) The storage restrictions under
5 28a.SO(a)(l) do not apply, and
(2) Such hazardous waste may be
disposed of in a landfill or surface *
impoundment, only if;
(i) This landfill if in interim state
meets the requirements of Subpart F of
Part 285 and § 285.301 {a} through Ce) of
(his chapter.
(ii) The landfill, if permitted, meats the
requirements of Swbpart F of Part 284
and § 264.301 (c) through f«s) of Jhis
t.hapter.
(Hi) The surface impoundment, if in
interim status, meets the requirmnpnts of
Suhpart F of Part 283 aad 1 265.221 (a)
through (e) of this chapter; or
(iv) The surface impoundment, if
permitted, meets the requirements of
Stiljparl F of Part 254 and § 284.321 (c)
through (ej of this chapter.
8268.S Petitions tesi&w Seng disposal of
a waste prefObtted under Suteiart C at Part
(a) Any person seeking a variance
from a prohibition under Subpart C of
this part for the disposal of a restricted
hazardous waste in a particular unit or
units must submit a petition to the
Administrator demonstrating that any
hazardous constituents of the waste are
at levels that ensure, to & reasonable
degre® of certainty, that them will b@ no
migration of any such hazardous
eoasiifjsaats of the waste from the area
of ®feetiv® control into the air, ground
water, surface water, or soil in
applicable screening level, or that result
in adverse effects upon the environment
(1) The Administrator will use the
following criteria for determining
whether the established screening levels
may be exceeded for any threshold
constituents:
teria:
(A) Other potential or actual sources
of exposure to the saraa or similar, *
esrasiitents.
(B) The lev®! and type of wncertainty
* potential exposure to th® surrounding
(is) lexicological criteria:
attributable -to a threshold constituent
(B) Tha fmpencyand magnitude of
potential gxpssEre to a threshold
constituent
(2) The Adraisjistestor will use the .
threshold constituents:
(i) Exposure criteria:
(A) Other potential er actual sources
of exposure to the same or similar
constituents.
(BJ Th® level and typg of uncertainty
inherent in the models issad to predict
potential exposure to th® surrounding
population.
(C) The potential current and future
risk to individuals from the activities of
the disposal asJt
{DJ The'size and nature of the
potentially exposed population.
[iij Toxicologies! criteria: the level
and type of uncertainty inherent in the
data used to estimate health risks.
(b) The demonstration referred to in
paragraph (a) of this section must
include an analysis of the total number
of-people that could potentially be
exposed to any hazardous constituent of
the specified wasts for as long as the
specified waste remains hazardous.
(c) The demonstration referred to in
paragraph (a) of this section must
include assurances that land disposal of
the specified wasts will not cause
adverse effects on any aquatic biota,
wildlife, vegetation, protected lands, or
other areas of potential ecological or
•economic significance.
(d) The demonstration referred to in
paragraphs (a), (b). and (e) of this
section may-include the following *
(1) An identification of th® specific
waste and the specific unit for which th
damonstratioa will be mads.
(2) A waste analysis, using methods
described in SW-S46, whsrs
appropriate, or equivalent methods
approved by the Administrate' in
accordance with i 2SQ.21 of this chapter,
to describe fully ths.cfiemieal and
physical characteristics of ttie subject
waste, including the waste's toxiraty,
mobility, persistence, and propensity to
bioaccumralate.
(3) An evaluation of the psrfcrraamce
(4) A .comprehensive characterization
of .th® disposal unit site and area of
effective control, including an analysis
of bsckgroBBd air, soil sisd water
quality.
(S) Predictions of th© ultimate fate of
hazardous con3titu@jits in the air., soil,
surfacs water, and gromsd water, at die
point ©? points of potential humess and
enviroaiaaatal exposurs.
(e) The demonstration rsfssred to in
paragraphs (a), (b). arad (c) of this
section must mest ths foOowing criteria:
sampling or test data must bs accurate.
(2) All sampling, testing, and
estimation techniques fc? chemical and
physical properties of the waste and all
environmental parameters must have
been approved by the Administrator.
(3) Simulation models may need to be
calibrated for the specific waste and site
conditions, and verified for accuracy by
comparison with actual measurements.
(4) A quality assurance and quality
control plan that addresses all aspects
of the demonstration must be approved
by the Administrator.
(5) An analysis may need to bs
performed to identify and quantify «ay •
aspects of the demonstration that
contribute significantly to uncertainty.
This analysis must include an
evaluation of the consequences of
predictable future events, including, but
not limited to earthquakes, floods.
severe storm evests. droughts, or other
natural phenomena.
(f) Each petition must foe submitted to
the Administrator bj» certified mail.
fg) Each petition must include the
following statement feigned by the
petitioner or an authorized
representative:
! «s;riify under jjanaiSy of !aw that! have
personally examined and am familiar wiih
the information submitted in this petition and
all attached documents, acid thai, based oii
my inquiry of those individuals issmadiatoiy
-------
11-4
Fagaau RBgaterV VoL SI. No. § / Trasaday. January 14>1986J^^S^^^^.
1783
i tot ofeteiifeg tkt fafetmatiea. 1
efcrtthsrihrattKlisfefissttoaistros
j*t«s«lco=pl:lil«=r«wmrathsJthsr
JK&KU pe^iss for sobntttiiw f»l«s •
-
jsMrator may request any •
inn|!nfoflcation the? ujay
!««*%• b«r»q*£md to evahale tha
•stealkn.
gapproved. th* petition will apply
ni«lijc*al of th* specific restricted
sa&tha fcsdirfcfcsl disposal unit
•afcsiia tba dteeosslraHoo end will
0B% to aayotiwr restricted waste
"Mrs AdmMsfeatoe shall give public
te«i tha intent to approve or deny a
MM sad provide an opportunity for
cenKicaLTita Administrator
gpwt public nottc* of th« goal
CIJThs Administrator will provide
sat8jotic3 to ins petitioner upon
aval or denial of a petition. If
3*«1 la given, the notice will
d&j> tin land disposal unit tha
KB tfwt may to dlsponed thmain,
petitfc
shall retain the
at fear tfa» tea of the approval as
itdby paragraph {1} of this section.
UK term of an approved petition
c be no longer than the term of the
Apermit if the disposal unit is
attafundtr * RCRA permit, or up to
latfnaam of 10 years freia.th* date of
taffia provided under paragraph
Jdfthis jaetfoa if tbs tmit is
a&og oadar intefia states. In either
„ ft* tena of tha appwrsd petition
Lt*pka opoa the termination or
aidT* RCRA permit, or upon tha
.iactiotx'of interim status or when
rafiana limit spctdfiad in tfa« petition
ached.
!.»
) The owner or operator of any land
osal facility accepting any waste
fret to restrictions under this part,
t h»va records of either the
boent ccrtiBcation spedfled in
igraph (b) of this section or of
idtnt wasta analysis through testing
ir waste for the constituents listed in
DrCCWE In i 263.42 to determine
itiut &• wastes are in compliance
atbe applicable treatment standards
rffitd in Sidjpart D of this part The
ilKSttist b« tested using the methods
cri&ed In SW-848 or equivalent
teds approved by tha Administrator
irrstdsnc* with jj 2CO20 asd 280^1
fd» chapter.
(b) Where ths applicable treatment
standard for a waste is treatment by a
specific technology (L&, 5 2S&41(a)j. the
owner or oparator of the treatment
facility most submit a certification to ths
land disposal facility stating that the
waata has beea treated using the .
specified tedinology. The certification is
subjsct ta &s following requirements:
' (1) The esTtSScatien must be signed by
tha ireater or his authorized
representative and must state the
following:
I certify uste paaa!ty of law that ! h*v« •
psmoaaBy ecasstasd and asa £*2xuliar with
ifaa trestctsnt tedmology aad operatttin of tha
treatmeat psrocess used to tappirt thin
ccrtiBc&tim wid th&t» basod 03 i&y isGjuiry of
those individaale toiz&iidSsteiy rssporuibls for
obtainiag this inlbmuidaa, I feslleve tlwt tfce
traaaaent pracesa has baen operated and
rcainUJBc-d-piiopcjiy go as to eeistevs the
trettEiat etmTsdards of tfes tpesiSssd
ffchEology without dilution of the piobibited
WEsSe. I era aware that there «ra signiBcant
p«9«ltie3 for submitting a false certification
including Ins possibility of fine and
unptteotmieat.
(2) Ths certification must be sent to
the land disposal facility before the
treated waste (including treatment
residues) is snipped bf the treats? and
most ba kept on sits for 3 years after the
wast* is cktK&d in a land disposal unit
at the facility.
J2SS4)
The following material is incorporated
by reference) and is available for
inspection at the Qffica of the Federal
Register Information Center. Rm. 3301,
11CO L Si, NW.. Wasfefegton. DC mm.
Thate incorporations by reference were
approved by tha Directs? of the Office of
ths Federal Register. Tha material is
incorporated as it exists on the date of
approval and a notics of any change in
the material win fea published in the
(a) Test Methods for Evaluating Solid
Waste. Physical/Chemical Methods,"
EPA Publication SW-846 (First Edition.
1S80. as updated by Revision A (August
1980), B Only 1881). and C (February
1982) or Second Edition, 1982). The first
edition of SW-646 is no longer in print
Revisions A and B are available from
NTIS, 5285 Port Royal Road, Springfield.
Virginia 22101. The second edition of
SW-843 includes materiel from the first
edition and Revisions A, B, and C its a
reorganized fciEiat It is available from
the Supertatedent of Documents, U.S. .
Government Pitatijig Office.
Washington. D.C. 20433 (232-752=3238).
on a eabscription basis, and futum
updates will antomaticaily be mailed to
the subscriber. Tha matsrial is cited in
the follsming sections of Fart 2Gfe
§§ 238.1(e)(2). 2fi&5(c)(2). 26&6(a). and
268.42(8}.
(b) {Reserved.}
3. By adding Subpart C to proposed
Part 233 to read as follows:
28130 Wasts specific prchibitiorw—Group
I
288.31 Waste specific prohibitioRS — Group
: o. .
§299^8
(a) Effective November 8. 19B8. the
wastes listed in paragraph (b) of this
section are prohibited from land
disposal, except in an injection well,
(1) The wastes are treated to meet the
standards of Subpart D of this part or
(2) The wastes are subject to a
successful petitioa under, f 2S&S. or
(3) An extension has been granted
under § 233.4.
(b) Prohibited are t2se following
solvent coateising wastes containing
great®? that i percent (by weight) total
• organic consasnessts, except for solvent
contaminated soils:
F001— The following spent halogenated
solvents used in degreasing:
tetrachloroethyiene,
trichloroethyiene, methylena
chloride, 1,1,1-oichloroethane.
carbon tetrachloride. and
chloftoated Sfflorooarbons; all spent
solvent mixtures/blends used in
degreasing containing, before use, a-
total of 10 percent or more (by
volume) of one or more of the above
halogeasted solvents or those
solvents listed in FOOE. F004. and
F895: and still bottoms from tha
recovery of these spent solvents
and spent solvent mixtures.
F002— The following spent halogenated
solvents: tetrachloroethylene.
methylene chloride.
trichloroethyiene. 1.1,1-
trichloroethane. chlorobenzene,
ortho-dichlorobsnsene, and
trichlorofluoromethane: ail spent
solvent mucturea/biends containing,
before us®, a total of 10 percent or
more (by volume) of one or more of
the above faalogtra&ted solvents or
those solvents listed in FOG1. FG04,
and FCOS; and still bottoms from the
recovery of thesa spent solvents
and spsat solvent mixtures.
FOOS— The following spsni non-
kalogenated solvents: xybne.
-------
U-5
1764
Federal Register / VoL 81. No. 9 /Tuesday.
acetone, ethyl acetate, athyl
bsBzane. ethyl ether, methyl
isobBtyi keiOES, a-butyl alcohol
(a) Eisctivs November a, 1983, the
sestto sra prohibited from land
disposal, except in sn injection well,
unless:
_r (l)Hie? wastes ara treated to meet the
containing, befoes ns«,'«8 as mof® standards of Subpart D of Ms part, or
of the above nen-Wiigsaatad (2) The Wastes ar® subject to a
solv8Bt8aaiEidat®taI®fi©ps2'ceator saesassM petition »B«t@r §288.5, or
mare (by volume) e£es«©? more of '"" " •—i—i*—
these solvents listed ia FOBS. MJ2.
F®JS, aad FOOSs and still bottoms t—j „..—__ —
November 8,1SSS, wastes identified ia
aarafraph (c) of this section may ba
disposed of ia a landfill or surface
nader 1283.4.
• sofcsats aad spent solvent
F004—The following speat non-
cfesylie add and tsitrobeaseae; all
spent solvent asixtares/felends
containing, before use, a tots! of 10
impcrmdmaat only if the facility is in
eempliaffiss with the miaimusa
PM2).
or mof@ of me above aon*
halogaaated solvents or those
solvents listed ia F001. FOQ2, aad
FOGS; aad still bottoms from the.
fscov&r/ of tliesa spent solvents
and spent solvent mixtures.
?00&—The following speat soa-
wasfc® (eosstainini less thaa 1 percent
\s&ff ww^sgjfta'fcj! at^^c^a •«t*jj»"«nii'n' ««i«i ••wa*v«
aim solvent contssninsted soils.
i—Tfas following gpeathaiogeimted
elslerfdss, l,U-
sootslnicg, before laae, m total of 10
1 percent or mcra (by volume) of ons
or more of the above ESE-
halogenated solvents o? those
solvents listed ia FOOi. F002, and
FQO$ and still bottoms from the
recovery of these speat solvents
aad solvent mixtures.
PG23—Carbea disulSde
UJHK—Asetaas
UQ31—-a-Butyl alsidsol
U037—The following spent non-
halogenated solvents: xylene.
acetone, ethyl acetate, ethyl
@, sthyl ethsr, methyl
e, &~bntyl alcohol,
ethanol; all
solely th© above spent
and all
-sjsssjt solvent mixturss/blsads
containing, before use. one or more
of ths above noa-hslogenated
solvents, and a total of 10 percent or
mor@ Cay volume) of one or more of
thesss g-alvEGJs listed ia F001. F002,
RSJ4. and FOSSs and still bottoms
feom the recovery of these spent
eolvente and spent solvent
FOM—iTh® following spent sson-
fealegeaated solvents: cresola and
eresyiie add and nitrobenzene: all
eoataissjng, before use, a total of 10
pescsisJ or more (by volume) of one
or more of the above non-
ilSUmgWSSsS**"1** «%*»W«»i»aw v* uutva»
solvents Usted in FOQ1. F002, and
FTO5; and still bottoms from the
recovery of these spent solvents
and spent solvent mixtures.
POOS—The followrai apsat non-
halogenatsd solvents: toluene,
methyl ethyl ketons, carbon
disiilSfe ieobtttaaol and pyridine;
gfi sp@iat golvent mixturea/blends
containing, before use. a total of 10
percent @r more (by volume) of one
or mam sf the above non-
Sffibfsmte listed to Hm. FOQ2. and
still bottoms feom tha
aad spent solvent mixtures.
UOQ2— Acetone
UC31 — a-Butyl slcohol
U037— Ghlorobesazene
UQ5&-*G?ssols and cresylic acid
UOS7— Cydohexanoae
U07Q— ®43ichlorobenzene
Ull2~Ethy! acetate
Uliy— Ethyl stfee?
Ul4Q-4sobutasol
U1S«— Meihanol
U1S8— Methyl ethyl ketone
UliS-^fethyl isobutyl ketone
Ul^— Nitrobenzene
U198»-?yridine
U210— Tetrachloroethylene
U211—Carbos tetrachloride
U220™ Toltsene
U228— 1.1.1-Trichloroethane
U228—Trichloraethyiene
U238— Xylens
(2) The following dioxion-contaming
wastes:
F020— Wastes (except wastewater and
sjsffiHt casbon&om hydrogen
chloride purification) from die
DfcdKKtioK affid msaufacturing uss
(as- a reaotaut, chemical
totsirss.edJate, as component in a
foraiiilatiRg process} of tri-, or
-------
XX-6
al Register / VoL 51. No. 9 / Tuesday. jaguary 14. 1§88 / Proposed Rules
176S
intermediates used to produce their
pesUdda derivatives. (This listing
does not include wattes from tha
production of hexachloropbsfie
from highly purified 2AS-
tricalorephtncL)
tm—-Wastea (except wastewater and
spent carboa from hydrogsn.
chloridt purification) from the
production or ms^ufaUuring us* (as
a nactent. chemical taicrmsdiates.
or component in a formulating .
process) of pentachlorophenoi. or of
intermediates used to produca its
derivatives.
332—Wastes (except vmstswater and
spent carbon from hydrogen
chlcrida purification} from the
manufacturing usa (as a teactant
chemical Intermediate, or
component in a formulating'
process) of to tra-, penta-. or
bexachlorobenzenes under alkaline
conditions.
J23—Wastes (except wastewater and
•pent carbon from hydrogen
chlorida purification) from the
production of materials on
equipment previously used for ths
production or manufacturing usa (ag
a reactant. chemical intemadiate.
or componaat in a fozmalating
process) of tri-, and
&fcmchlaroph*sol*. (This Hating
does not include wastes from
equipment used only for the
production or use of
bexachlorophene made from highly
purified 2.4,5-trlchlorophsnoL)
X2B—Wastes (except wastewater and
spent carbon from hydrogen
chloride purification) from ths '
production of materials on
equipment previously us«d for the
Manufacturing use (as a reactant,
chemical intermediate, or
component in a formulation
process) of tetra-. penta-, or
bexachlorobenzeno under alkaline
conditions.
tZT—Discarded unused formulations
containing tri-. tetra- or
pentachlorophenoi. or compounds
derived from these chlorophenols.
{This listing does not include
formulations containing
bexachlorophene synthesized from
prepurified 2.4.5-trichlorophenol as
the sole component)
4. By adding Subpart D to proposed
irt 208 to read as follows:
Apart D—Tr««!n»int SJanetete
SK.
2S3.42 Treatment levels expressed a*
eonssntoatiooa in waala ax tract
268.43 Twatewnt standards expressed as
waste coacentradsn*. (Reserved]
Syfepsst O—Tf*atos««Bt StsndsrcSs
AppIfcabiUtyoftraatmtntstandsnis.
941 Treatment standards cxprosied as a
specified technology.
(a) Prior to land disposal, any waste
for which an identified technology is
specified as tha treatment standard
§ 288.41(a), must be treated using that
technology or treated using an
equivalent treatment method approved
by the Administrator or under the
procedures set forth hi ! 28&41(b),
unless the hazardous constituents in an
extract of the waste or in the Waste are
less than tha concentration levels
indicated in § 26&42 or § 288.43,
respectively.
(b) For land disposal of a waste listed
in Subpart C of this part but not
specifically identified in § 283.43, the
concentrations of hazardous
constituents in the waste extract must
not equal or exceed the value given for
any hazardous constituent listed in
Table CCWE in f268.42(a). If none of
tha concentrations of hazardous
coastitasn«s in tha waste extract equal
o? exceed the specified concentrations
listed fa Table CCWE in 1288.42(a). ths
wasta may fas land disposed without
further treatment If the concentration of
any.hasardous constituent in the waste
extract equals or exceeds a level
indicated in Table CCWE in § 288.42(a)/
for that constituent the waste must
undergo treatment to bring the level
below ths applicable concentration level
before being land disposed.
§.2S&41 Treatesrt stegxta&s exprcmMi
as a tpswWM tecfmlasy.
(a) The following wastes must be
treated using ths identified technology
or technologies, or aa equivalent method
approved by ths Assistant '.
Administrator for Solid Waste and
Emergency Response:
[Wastes and designated treatment
•technologies will be specified in future
actions.]
(b) Any person may submit an
application to the Assistant
Administrator for Solid Waste and
Emergency Response demonstrating that
an alternative treatment method can
achieve a level of performance
equivalent to that achieved by methods
spedfiKl in paragraph (a) of thie section.
The applicant must show that his
treatment method will not present an
unreasonable risk of injury to health or
tha environment. On the basis oif such
information and any other available
information, the Assistant Administrator
for Solid Wasts amd Emergency
Response may; In his discretion.
approve the us® cf the alternative
treatment slatted if h@ feds, that the
altem®«lws treatment method provides a
level of perferaiane® equivalent to that
achieved by methods specified in
paragraph (a) of this section. Any
approval muat be stated in writing and
may contain suds provisions and
conditions as the Assistant
Administrator for Solid Waste and
Emergency Respena® deems
appropriate. The person to whom such
certification ia issued must comply with
all limitations coatated in such
determinatiao.
§268,43 TMsteseBttmtta®8$w®*3e«»as
68M6®SB$iWttei® te W4JH&© 9Zt?@€tn
Using fe test methods described in
SW-S4S or eqmivaiemt methods
approved by the Administrator under
the premium act forth in § 128O2Q and
230.21 of this chapter, the extract from a
representative sampia of a waste
identified in Subpart C of this part, or
from the residue of treatment of such a
waste, must not contain any of the
Cflratitizesta listed in Tabls CCWE at a
conceutratim greater than the
rsspectiv@ value gjV«a ia that table.
Whfiss &@ waste contains leas than 0.5
percent filterable solids, the waste itself,
tafter filtering, is considered to be the
extract for the purposes of this section.
TASLE CCWE—COMSTTTUSNT CONCENTRATION
IN WASTE EXTRACT
Cot
CS*JSSt®telHES®B™
CresaSB
M*ttiyl iwtwtyt txtona
piiCOD'^Ag PaCTaaefU@godiiS
PeCOP-*a
tmofHtonoas..
Totwra.
Trfe^toflQ^sc^rooaWfWi®™
3.4.S Tri
Z.4.STm
2.0
ZO
20
0.1
2.0
2.0
2.0
2.0
2.0
.001 l
.001 I
20
2.0
1.2
2.0
2.0
0.09
.001 (usai
.001 ;ippei
1.0
.001 {
.001 dppft)
0.013
10
2.0
2.0
2.0
0.1
2.0
8.0
0.04
2.0
-------
-f
II-7
1766 Federal Isgbtsr / VoL 51. No. 9 / Tuesday. January 14. 1986 / Proposed Rates
§288.43
s» wast* concentrations. [Reserved]
5. By adding Subpart E consisting at
this time of § 26&50 to proposed Part 268
to read aa follows:
Subpart E— PraM&ifons en Stof«g«
restricted wcstss.
(a) A hazardous waste prohibited
from land disposal wader Subpart C of
this part may sot b* stead la tanks or
containers after the prohibition effective
date unless:
(1) Tha owner or operator of a
hazardous waste treatment, storage, or
disposal facility stores such waste for 90
days or less: or
(2) A transporter stores manifested
shipments of such waste in containers at
a transfer facility for 10 days or less; or,
(3) Such waste is accumulated on site
by the generator and does not exceed
the applicable time limitations set forth
in § 282.34 of this chapter.
(b) The prohibition in' paragraph (a) of
this section does not apply to the
conditions of an approved petition under
S 28&S or an approved casa-by-case
exteasion under i 28a4.
this section does not apply to hazardous
wastes that maet tha treatment
standards specified udder Subpart D of
this part.
-------
-------
APPENDIX III
AGENCY RISK ASSESSMENT
GUIDELINES
-------
-------
Wednesday
January 9, 1985
Part til
Environmental
Protection Agency
Proposed Guidelines for the Health Risk
Assessment of Chemical Mixtures and
Request for Comments; Notice
-------
•V, \tyF,!"
•• 4'H'"
1178
xiz-2 -
Federal Register / VoL SO. No. 6 / Wednesday. January a. l§8§ /
AGENCY
tPm.-2742-Sl
fifsk A*»i«3is«fit of CtoMfeaS Mxttno
« Environmental ^Protection
AgeacyfEPA. ,
Aenote Proposed gu!da'L?*s for the •
Health Risk Attesment of Chemical
Mtxtum and request foe cummenta.
mmtUOftt Tie UJ3. Enviranmsalal
Pro tectkm Agency is proposing
Guideline for the Ha*!thRiak
AsMssmnt of Chmtel Mixtures
(Guidelines). Tbssa Guidelines ere
proposed for usa within tha policy and
pir iedural framawork provided by tha
variow statutes that EPA administers to
guide Agency analysis of hoslth effects
data. Wa solicit public commimt and
.will take public comment into account in
revising tntsa Guidelines. These
Guidelines will be reviewed by the
Stienctt Advisory Board in meetings
cow tentatively scheduled for April
1985.,
These proposed Guidelines were
developed as part of a board guidelines
daveJopiatnt program und*; tha
auspices of tha Offics of Health and
Eaviroomsntal Assemcsot (OHEA).
located in the Agency's Office of
Research and Development Consonant
with ths role of OHEA's Environmental
Criteria and Assessment Office in
Cincinnati (ECAO-Cin) as the Agency's
senior health cbmmittea for health risk
assessment of chemical mixtures, the
Guldtlimawcradavalopcdbyan
Afaacy-wida working group chaired by
tha Director of ECAO-CIn.
DATE Comments must ba postmarked
by March 11,1885.
AOOfttss: Commants may ba mailed at
delivered to: Dr. Jerry Stara.
• Ehvironmental Criteria and Assessment
Office, U.S. Environmental Protection
Agency, 28 West St Clair. Cincinnati,
OH 45288.
FOR PUKTHEK mFOffMATMN CONTACT:
Dr. Richard Hertzber, Telephone: 513-
684-7551.
Preliminary drafts of these Guidelines
ware sent for review to approximately
20 scientists in the fields of toxicology,
pbarmacoldnetics and statistics within
the Agency and a later draft was sent
for external review to 12 scientists
within government, academia and the
private sector. Comments received from
these reviewers, generally favorable,
were considered in developing the
Guidelines proposed here.
Refemafiss and supporting cbosm&ats
used is tha preparation of these
guidsliaos aa well as comments received-
are avaiHabte for inspection and copying
at the Public Information Reference Unit
(202-382-5828), EPA Haadquattea
Library. 401M Street SW, Washington.
DC batwaea tha hours of 8X0 sum. and
Detod: January X UWS.
i fclroidiscttoa
Q, Ptopsisd approach '
A. Data AvaUobla oa similar ra&taio*
& Data Avauahia onif oo Mxture
t. Syatemie Toxicants
3. GsreJnogena
4. UacsrtaiaKe*
a. Health EEccts
* b. Exposure Uncsrteintisa
* e, Unc8rt«inKca Regarding
Ccjcsposition of tha &fixtnr«
Et AmisiptioEj and LuniUtiona
IV. Mathematical Models and the
MteaaKoseaJ of Joint Action
A. Dos* Addition
B. BaapouM Addition
V.
The primary purposs of thia document
is to generate a ccmsfetent Agency
approach for evaluating data oil the
chronic and subchronic effects of
chemical mixtures. It is a procedural
guide which emphasizes broad
underlying principles of the various
science diadplinss (toxicology.
pharmacology, statistics) necessary for
assessing health risk from chemical
mixture oxposum. Approaches to be
osad with respect to the analysis and
evaluation of the various data tire also
discussed.
It is not tha intent of these Guidelines
to regulate any social or economic
aspects concerning risk of injury to
human health or the environment
caused by exposure to a chemical
agents(s). All such action is addressed
hi specific statutes and federal
legislation and is independent of these
Guidelines.
While some potential environmental
hazards involve significant exposure to
only a single compound, most instances
of environmental contamination involve
concurrent or sequential exposures to a
variety us compounds that my induce
similar or dissimilar effects over
exposure periods ranging from short-
terra to lifetime. In some instances, the
mixtures are highly complex consisting
of scores of compounds that are
geaafatsd sSsauliaseoiisly aa by- • :
preduais from a sfcgls source or process
(&gc, coke ovos emissions and diesel
exEsustJ. la other eases, complex
mixtures ofwrlatsd compounds are
- prodtsesd as commercial products (e.g.,
PCS*, gasoltea assd pesMside
foratdaitasj ami eventually released to
the @Qvteame3& Another class of • :::
mixtures eeoalsta of compounds, often
which are ptecsd in the same area for
digfjcsel or steage. eventually come
too contact with each other, and am
released as a mixture to the
eaviroESESBt, Tits quality and quantity
of pertesat istemation available for
risk .ansasemefflt varies considerably far -
• different mixtee*. Occasionally, the
chsf&icid coinpositioras of & mixture is
well chafxcteked, levels of exposure to
the population are known, and detailed
toxicologta data on the Mixture are
svaikbls. Most frequently, not all
components of the mixtutcs are known,
exposure data are uncertain, and
toxicologic data on ths known
components of the mixture are limited.
Nonetheless, the Agency may be
required to take action because of the
number of individual st potential risk or
beeaoss of tb& kuowra tojdcologie effects
of thsm easnparufflda that have been
Identified in the miKtura. .
, - Guidalines £9? aingie .compound risk
' sssessmeBts have been developed for
subchroxue and chronic exposures to
both systemic toxicants and
carcinogens. In the current document •
these approaches are extended to
provide compatible guidelines for
assessing die effects of multiple toxicant
or multiple eaedaogea exposures.
The ability ts predict how specific
mixtures of tamomta will interact must
be based out aa understanding of the
mschsoi&ms of such interactions. Most
reviewa and texts that discuss toxicant
interactions usake some attempt to
dissuss the biological or chemical bases
of the interaetioas (e.g* KJsassen and
DoulL 1S6Q; Leviaa, 1973: Goldstein et
aL. 1074; NEC 1980s; Veldstra. 1953;
Withey. 1SS1|. Although different
. authors use somewhat different
classification schemes for discussing the
ways in which toxicants interact it
generally is recognized that toxicant
interactions may occur during any of the
toxicologic processes that take place
with a single compound: absorption,
distribution. mstebcJism, excretion, and
activity at the receptor site(a). to
addition, compounds may interact
chemically, causing a change in tha
biological effeeS or they may interact by
causing different effects at different
receptor sites. . <
-------
Fe&szdl Refissies / VoL 801 No. 8. /. Wednesday. January 9. 188J /Noticas
1131
Because of the une«ftataties iahsrsat
in any approach to predicting the
magnitBds and nature of toxicant
i&teractioas, aav assaaarasat si haaith
risk from ehemicd zaixturg most ioduds
assumptions. Ho stogia approach is
OJ SSS &&&&X9 OS
!a ta ea rasarsi c3
en a* SJfenrasa la cssttsfrasa.
a few simple dppk3*diai invohrisg-iiik
addition a? desss addition. Yha
i Be BBfc das
Section IV.
4, A68*s data co tnaareeBeta o). eaBgatreaa K-fiw
messforeanH) e) tea w «era
- - -
recommsadgd t@ sfek-asssassisats fo?
ftre, sssreje » >
availability of toxidty data ea tfee
mixture or eteilg? eslxtissss, tfes knswa
or anticipated mtefsetkras ammg
components ia the mixture, arid tha
quality of the essposmfs data. Gives the
complexity of this issas and the relative
paucity of esipMcsi data feera which
sousd geaajaHsaaesa esa fes
?. Use «n
fteota* (9 Stsp &
tta
of as
esupaaA «n unras
Similarly, if the risk assessment is
- tod
\m
ea SsodbiJiSy, JadpEeaf. essd s dase
SsassyriE&agsse?S!sattlsat& dsta-to a jfefe aasesfHssst atea to
developed, The proposed approach is
iummartEsd la Table 1 and detailed
below.
A. Data Available on Similar Mixtures
For predicting tha effects el
diminished. This eaa be ofest to MKM®
uae sebehroaic er efaccais health effesta
data os tha mixtoa of csES^a esd
mixtures of the same components but
hav&of different ratios of tha
components which encompass the
diffswsRES is esmpositios seea with
time QS taa diSereat ssssfSSJOB sources,
If such data are available, am attempt
should be raads t@ daterm&ta if
significant and systematic differanees
esdst among the.chemicai mixtures. If
sigrJISesat difiersnssa are noted, ranges
data are most likely to be svailabk on
highly cooipl
oven emissica or diesel eKhasist h&
are generated ia large quantities ®»3
associated with or msspeeted of having
advene health effects. Ewea if sash data
are available, attention should ba pven
to the persistence of tha mixture ia the
environment as well as the variability of
composition of the mixture over time or
from different sources of emission*. H
the components in the mixture gre
known to partition into different
environmental compartments or to
degrade or transform at different rates
in the environment, then thosa faeiara
most also b® ta&ea into account, or th@
confidence is and applic-abJlity cf the
risk aasesamerat is diminished.
of risk can be estimated based oss
tosdcoJogic data from the various
mixtures. If no significant differaraess
are noted, then a single risk assessment
may be adequate, although soms
statement should be made giving th®
range of ratios of the components iss the
mixtures to which the risk assessment
applies.
mixruresof concern but health effects
data ara available on a similar mixture
(i.e.. e mixture having the same
components but at slightly different
ratios, as having several comracm
components but lacking one or more
components, c? having one or more
additional componenta] a deoeicm must
b@ made whether the zssjxtwje era which
health effects data are available is or is
not "sufficiently similar" to the mixture
of concsra to psnait a risk assessment
Th® dsterajiaation of "sufficient.
similarity" mast ba mad® on a caae-by-
caaa basis, eaasideriEg not only the
iHscsrtsiatisa aa&ssiatad with using data
OH a disaimilar mixtura but also the
unesrtainttea of ssing approaches based
aa-additivity, which ars detailed later.
la dsterminfejg reasonable similarity,
ecnsideratioa shoald b® given, to any
informatios ess tisa components which
differ -tw ar® contained is markedly
different proportions between the
mixture on which health effects data are
available? snd the mixture of concern.
B. Data Avaiitsbls OsJy oa Mixture
Components
If data are not available on an
identical or fsascsabiy similar mixture,
tSi® sisk assessment^aay be used OR the
toxie o? carcinogenic properties of She
compOBsata in ms zaixture. When little
©rno qoantitative information is
available on th®^^ potential interaction
amsng the ccnpsaents, doae additive
models are recomuseaded for systemic
toxicants (defined later). Several studies
have demonstrated that dose additive
models often predict reasonably well
gobstsetiai varfeif rfboih sissilas and
188CJ. Tfee problem of multiple toxicant
exposure has bsen addressed by the
Americais Gostfefemcs of Governmental
Industrial Hygieaiats (ACGLH, 1983). the
Occupational Safety and Health
Administration (OSHA, 1SS3], the World
Health Organization (WHO. 1981), and
tha National Research ^uneil (NRC,
1^8a^|. Although tha fecua «nd
all groups that recommended
an a
of do^ additive madeL Nonetheless. a@
discussed in Section IV. does additive
models are not the most biologically
plausible appsaack'if the compounds do
not have tha sama mode of toxicalogic
action. Consequently, depending on the
nature of the risk assessment and the
available mformation or modes of action
and patterns of joint action, the most
reasonable additive model should be
used.
1. Sjfsteasis Toxicassta .
For -sysisiaks toxicante. the current
risk assessment methodology used by
the agency for single compounds moat
often results in the derivation of an
expoerae iavel which is considered
acceptable or which is not anticipated to
cause adverse effects. Depending oa the
route of exposure, media of concern, aad
the legislative mandate guiding the risk •
-------
III-4
1172
fjrianJ Itegste? / VoL JjMlo. 6 I
. t
all. tha exposure kvals may ba
HWfiffV^'..pJgHI >< Ufli Wrt&^ufW^ftftTT *W»^k**» Ham iiinj w
expressed fa * variety of ways such as
Aeorpiabl* Daily fcUkei (ADb), levels
•ssodatsd with various Margfcs Of
Safety (MOS). or Ambiost Air
Standards. Foe tfta parpowi of this
dEtcosaioct, tbs tarn "AccspUbls Lover
(AL) wifl be«scd to toasts any of the
criteria, stekiards. ocedviiifflrtes derived
by the Agtacsr. For SJS- •»timata. th«
"hazard tatax* (HI) of s mixton basso
on th* awMiapaoii of dost sdditMty
maybe defined *E
H-E,/AL,+Ei/Al4+-+ E^AJ, OH)
todoieJ.
tadcsat
JInes ths Znvers* of ths acceptable Isvel
can ba used as an estimate of toxie
potency. Equation IM can bs interpfated
as a normalized weighted-avstafs docs.
with each ccmpomfit doaa scaled by its
potency. As this index approaches unity.
ecocaia foe tb.8 potential hazard of th®
mixture increases. If M>1. the concern
for the potential hazard is ths earns as if
an acceptable Isvel were excaeded for
an individual compound, La- if E,/AL,
exceeded 1. If the variabilities of the
accaptabla levels are known, or if the
accspUbla lavria ara giv«s as rangas
{*&, associated with diffonnt margins
of safety), than HI should be prenentod
with estimates of variation or as a
*^ hazard index is not a
mathematical prediction of incidence of
effects or severity. Statistical properties
of this index and its dependence on the
shape of tha do**-*6sponta corves for
tfca component* are not yet known.
Mcch additiooiil netsarch is required to
dtttimin* tht tcearacy of th« hazard
iodax aa a nnmaioil pwdlctioa of tando
severity. The hazard indas is only a
nmtfrical indicator of ths transition
betwetn acceptable and unacceptable
expotur* tovds and should not b»
As discussed in Section IV, ths
assumption of additivity is most
properly applied to compounds that
induce the same effect by the same
mechanism. Consequently, ths
application of Equation n-1 to a mixture
of compounds that does not interact and
is not expected to induce the same types
of effects could overestimate hazard.
Ihus. if the application of Equation n-1
results in an index near to or greater
than unity. It may be desirable to
segregate the compounds in the mixture
by critical effect and derive separate
indices for each effect. Conversely, if the
dissimilar effects influence one another
te-S, liver failure diminishing the
fnocttoa cf another organ), then simple
dose addition could underestimate ths .
total hesafd; tM» is discussed more fully
Sectioa IV, ox modifications of these
1^3 Agasiey has developed methods
fa? estimating dose-response curves for
single chemicals. e.g. cardnogens (U^.
EPA. 1S34}. In attempting to amsso tha
raipssss to mixaires using doss-
ths mixture, dosa-fidditiva or response»
addiUve assumptions can be usod, with
pfe&msa given to tha most biologically
plausible assumption.
& Carcinogens
For cardnogans, whenever linearity of
tha decs-response curve can be assumed
(osualy restricted to low doses], .tha
increase in incremental risk P. caused
by exposure d. ie related to cardnogenie
p.dB. (0-2)
For multipiQ compounds, thia equation
maybe generalized to:
P-SdjB,. (D-3)
Thia equation assumes independence of
action by ths several carcinogens and is
equivalent to the assumption of dose
addition as well as to response addition
with completely negative correlation of
telcrasea (see Sactiora IV). Analogous to
the pfo^edure tw@d in Equation; H-1 fo?
eystamic toxicants, an index could be
derolopad by dividing exposure levels
(SJ-by dosas (OR) associated with
varying levels of risk:
HI ~ Ei/BB, 4- Es/DR, + . . . » E,/OR>
(0-4)
It should ba emphasized that because of
ths uncertainties in estimating doss
response relationships for single
compounds and the additional
Encsrtainttes in combining ins
individual estimate to assens response
from exposure to mixtures, response
rates and hazard indices may have merit
in comparing risks but should not bs
regarded as measures of absolute risk.
3. Interactions .
Nous of the above equations
incorporates any form of synergistic or
antagonistic interaction. Some types of
information, however, may be available
that suggest that two or more
components in the mixture may interact
Such information must be assessed in
terms of both its relevance to subchronic
or chronic hazard and its suitability for
quantitatively altering the risk
-
For example, if chronic or subchronic
toxicity or cardnogenicity studies have'
been 'conducted that permit a
quantitative estimation of interaction for
two chemicals, then it may be desirabk
to consider using equation!) detailed in
as & Bioglss toxicant with greater or
from sdditMty. Other compounds in the
mixtw®. m which no such interaction
date so® available, could then be treated
In at additive manner. Befora such a
procsdra@ i® adopted, however, e
discussion should be presented of the
mixture may inteifsrs with sh«
iatorasHos of fes two toxicasste on
which quantitative interaction data ara
availaWa Bf ths weight of evidence
suggeats feat intsrferessca ia likely, then
an attempt to quaxttitstivsly alter ths
risk araemaeat may not b® justified. In
such eases, ths discraiion of the risk
aEwasraaat may only indicate ths likely
.. nature of interactioaa. either synergistic
or antagonistis, but not attempt to
.V« -• »•. . J_ _* *!_•_
mtemctiois.
O&es types of avaiiabls information,
auch as thosa relating to mechanisms of
toxicant interaction; or quantitative
estimates of interaction between two
chemicals derived from acute studies,
are «vea Issa likely to bs of quantitative
use in the asssssraaaC of long-term
health risks. Usually !8 will ba
the IsiajsEsiHea to srofeslscmc or chronic
possible, ths nature of my potential
interaction, without attempting to
quantify the magnitude of the
interaction.
4. Uncertainties
inadequate to assess tsxposura to human
populations as ths potential health
effects of one esr more components of the
mixtars. M such a case, the leas studied
harmless. Instead the uncertainty is
increased. Confidence im the risk
assessment is rsdacsd because tha
contributioii af these componenta to the
toxicity of ths mixture and.
consequently, the toxicity of the mixture
itsslf are not known.
a. Health Effects. !n some cases, when
health effects data are incomplete, it
may be possible to argue by analog}' or
quantitative struetura-activity
relationshipa that ths compounds on
which no hselth effects data are
available am s»t likely to significantly
affect tile texJea'iy of the mixture. If a
risk a$83S/sasMse is conducted based on
such @a argKsasMi, the Iteiiiationa of the
approach mess be deasiy articulated.
-------
HI-5
/ Volsa No: 8 / Wednesday. January. S. 1985. / Notices
1173
Since s msthsdbisgF has act bom
adopted for estimating an acceptable
lave! (®.g» ADI) os carsinsgeme potency
tern •cnening tests, svsh methods am
mixtures.
b. &qseaww CfewteMsa It lewis of •
8xpostM8 to esrtala sompausds kaowit
to bs in the misstate srs net available,'
psratsteiea and transport
that these compounds ara not
likely to be sigsdScsixt-is. afectiag Ska
toxidty of the ssiixtuzs, them a risk
assessment can bs eradected based en
the MHMfaiing eosspffiBade in the
mixture, with appropriate eavaats. If
no final risk agaaeaaisat esa fee
data are available. As SB tateriM
procedure, a risk assessment may bs
conducted for thss® components in ifa®
mixture for whiids adequate exposure:
and health effects data arc available. If
ths results of the iniaria dak
already exists, rea®assis stiglat be b@ttss
axps&dad ea resssdlsl asHoa as p&ft of
than on further sasesasaeat. Coassm ia/
not redossd if the iatedot dak
mixture hava been considered.
a Uncertainties Regarding
Composition of th® Mix&irts, As a we*s4
Ea'ddag not oniy on hssith sffasts sad
described ia ths pnwieaa paiagsaph, sa
affects and exposasa iafcraaatica ars
available. If a hazard is iadieated,
be carefully qualified to avoid OTS?
interpretation of th@ ecemas^r of ths
assessment. If no hazard is indicated,
the risk asgessmisat should aot bs
quantified until better health effects and
monitoring data are available.
HL AsssaaapSlcas aasd Umitatiims
Most of ths data available on toxicant
interactions are derived &raa aeate
tajddty studies asing experirae&tel '
animafs ia which saixtess of two
compounds WS-ES tested often is onljr a
single cosabmatioa. Mafor areas of
uncertainty with mssh data involve &s
appropriateness of interaction date from
an aaate toxidty study to quantitatively
ales? a risk assessment for subchroaic or
ehraaie sxposure, the appropriateness-of
toteastioa data OK two component
mixtures to quantitatively alter a risk
essesjsmant on a mixture; of several
eompounda. and the prsdictability of
to quantitatively assess
tetsractions in hnmans.
Tfee use of interaction data from acuta
toxicity studies to asseae ths potential
tefsmetions OB chronic exposure would
b© highly questionable unless the
machanism(e} of ths interaction on acute
expasisra were known to apply to low
doss chronic exposure. However, most
Mo^n biological medjsnisma for
tojdcaat interactions involve som® fona
of competition between ths chemieala or
phenomena involving saturation of a
^ssptor site or metabolis pathway. As
the doses of tiie toxicants ara decreased,
ii is likely that thes@ mechanisms either
no longer will exert a significant effect
o? will be decreased to an extent which
cannot be measured or approximated.
The sase of information from two
component mixnirea; to assess the
totefsetioazis m mixture containing
ecsss|3t!!ands.«9rgi JosowB" Jo interact, either
synergistically sr antagonistically.
basauss of the effects of oss compound
on the mataboliam o? excretion of the
other, ths addition of a third compound
which either chemically alters or affects
the ailbsospaoa of one of the first two;
campomds cotsld substantially alter the
degree of th® toxicoiogie interaction.
Usually. dataUed studies quantifying
tosde&Et int^aetioap are not available
t miKtures,*andthe
t ass. available on such
rabcturas (e.g» Golliao et at, 1S59) do not
provide sufficient information to assess
the effects of interactive intetference.
Concsms with the u*a of interaction
data on experimantal mammals to
assess interactions in humans is based
on the increasing appreciation for
systematic differences among spedes in
their response to individual chemicals. If
systematiis differences in intes^pedes
sensitivity exist among species, then it
seems reasonable to suggest that the
magnitude of toxicant interactions-
among spedes also may vary in a
z~fSZesm&&msamG£. Comsequsntly. even
If ®kcallaat chnmis data are available
oa tha magnitude of toxicant
intaractioiu in a spades of experimental
Essmffissi. ther@ is unceftainiy thet the
usagnsteds of th@ interaction will be the
same in humans. Again, data are not
available to propsriy assess the _
eiiniSeancs of this uncertainty.
Last,it:§hs8uld.b8 emphasizsd that
uoa® of ths, models for toxicant
interaction can predict the magnitude of
toxicant interactions in th® absence of
extensive data. If sufficient data are,
available to estimate interactive
coefficients as dssciibed ia Section IV.
th@Q-dig asagoitKd® of the toxicant
interactions for various proportions, of
the gams components can bs predicted.
The availability of an interaction ratio
• (observed response divided by predicted
response) is useful only in asssssing the
magnitude of the toxicant intcrastion for
ths specific proportions of the mixture
which were usad to generate the
Interaetion ratis.
The basic assumption in ths
recommended approach is the risk
assessments on'Chemical, mixtures are
best conducted using toxicoiogie data on
similar mixture. While such risk
assessments do not fomaally consider
toxieologic interactions as part of a
mathematic model, it is assumed that
responses in experimental mammals or
human populations noted after exposure
to ths chamical mixture ess bs used to
coadact risk'-asoeannenti on human,
mixturea using ;8xperimental mazmnals.
the same limitations inherent in species*
to-spsdea extrapolation for single
compounds apply to mixtures. "When
using health effects data on cheioicai
mixtures: from studies on exposed
human:populations, the limitations of
epidsmiologic studies in the risk
fflsssssESJTit of single compounds also
apply to mixtures. Additional limitations
effects data os cfaexaical mixtures-if the
components in the mixture are not
constant or if the components partition
in,the enviroi!!EJ2Et
If sufSdeat data are not available ,on
the effects of the chemical mixtor@ of
concern or a s
the proposed approach is to assunis
additivity. Dose addiiivity is based OR
the assumption that the components in
the mixture have the same mode of
action and elicit the same effects. This
assumption will not hold true in most
cases, .at least for mixtures of systemic
toxicants. For systemic toxicants,
however, most single compound risk,
assessments will result in the derivation
of accsptabla levels, which, as currently
defined, esuasst bs adapted to the
different forms of response additivity as
described to Section IV,
. Additivity models can be modiSed to
incorporate quantitative data on
toxisamt interactions from subchronic or
-------
nx-6
1174
F0d«al Rsgfete / Vat SS, No. 8 / Wednesday, January 9, !«/ Notices
^^ ""• 0 » _ . - .. . „. i,n.m...n.i.i.r.-i. i jm.iiiiiiiimijm.iiiiiiirinniiiniliunilil.r--n nil II I II LIUUIBIimH.!!--;—TTHPItP
cfcrenic stadias using the vtcdda givsa
wodtls. If thl* approach is Uktn,
fcotc3vsr.it will be ucd-!?tha«ssaE3pilo3
that other compoomts ia tfea niastsia do
•etfciCtrtei with tt-s auaunand
or chronic iateraeltesis data seldom will
bat awflmhl*. and meat jiek AHMMsratB,
ia tba abstes* of fccaJli «fiKU data on
tia aiixhira of caaora!, wi'l bt based oa
mat smsssstioa additivtty.
Dota-eddittva and refpsaw-jsiditiva
to substantial
•xron ia dak astimatM if «ptaf^§tic or
ssWivn to predlit the aen&t tiixioitte* of
•May mixtures of similar and dissimilar
uasjponnds (&g« Pozsani et aL. IKS:
Sasyih at «]., laes, 1870: Muipby. 1S30),
•cm marked exceptions have bssa
acted. For example. Smyth «t «!. (1S70)
ttttsd the teteractioa of 53 pair* of
ieebstri«l chemicals bassd oo aeat«
Itihsllty in rats. Few most pairs of
ccsnpouada. the ratio of the predicted
LDi» lo observed LDw did not vary by
njcra than * factor of 2. Tha greatest
variation was sean with as eqohroimas
jg^xtura of morpholine aod tolasas, in
wfeldi ths obs^vsd LDt* was about 2va
tins Itss than the OX* pssdictcd by
time additton. Ia a stady by HaiaiB«sd
«t«L (1878), tba relative risi of BJEJ
CS32CS- atttibutabk to amokins was 11.
while the relative risk associated with
asbestos exposure was 5. The relative
rick of King cancer from both smoking
mod aibestos exposure was 53, •
indicating a substantial synsrgistic
effect Consequently, hi sorna cases,
mJditiwity assumptions may
••iNrtantially ondenstiniate risk. In
e&w casts, risk may be overeBtbnated.
While this is certainly an unsatisfactory
fcHJUtion, it is a Hmitation associated
•ore with the nature and quality of the
available data on toxicant istersetioa
dura with the proposed appfocdt itsttli
IV. Mathematical Moduli md &a
The simplest mathematical models for
Joint action assume no interaction in
any mathematical sense. They describe
cither dose addition or response
addition and are motivated by data oa
acute lethal effects of mixtures of two
compounds.
A. Dose Addition
Dot« addition assumes that the '
toxicants hi a mixture behave as if they
were dilutions or concentrations of each •
ether, thus the slopes of the dota-
response curves for the individual
compounds are identical, and the
response elicited by the mixture can be
predicted by sommnig the individual
dcecs after adjusting fopdifeBBSMi« in
pattaeys this is defined as the ratio of
•quitoxis dosss. Probit transtaiiffi&m
typically stakes this ratio coiistsssJ at ail
doeea whss parallel straight HcSs are
obtained. Aitbongh this assufstistioa esn
be applied to any modal («,&, afej (that is
wha) is meant by equitedc dosas). Ia
this example, the pttta^y. p, is
apprcbdmttaly 2. Dose additioa assumes
that the response, Y, to any mixture of
these two toxicants can bs predicted by:
Y-03-i-3 log (Z> H-pZ>)
Thus, «ia"3s p is defined as Zi/Zi.
Equation IV-3 esssnfially converts Zt
into E25 sqawaJeffit doae of % by
adhiatiiQ for te diffcssEcs iia pSsEcy.
A mam gs?.«faifead fona of ihis
«juafisa for aay asember of tadcants im
where at is tisa y-intsrcept of the does-
response equation for toxicant-i. b is the
slope of the dosa-respoass lines for the
toxicants, & is tha proportion of the i8*
toxicant in the mixture. Pi is taa potency
of the i^-tSoxicant with respaei to
toxicant-! (Zi/Zt), and Z is the som of
die individual doses ia tha interne. A
znai-e detailed discussion of the
derivation of the equations for doss
addition is presmated by Fbmey (1971).
& Rmpansa Additie®
Ths other fbrsa of additivity is
refeKfsd to as reapotssa addiiHos. As
detailed by Bliss (1939), this type of joint
action assumes that the two toxicants
act on different receptor systems and
that ths correlation of individual
tolerances may range from completely
negative (r» —1) to completely positive
(r» +1) correlation. Responsa additios
assumes that the response to a given
concentration of a mixture of toxicants
ia completely determined by ths
fmyn&Ka to the components and tha
correktioa coaffidcnt. Taking P as the
proportion of organisms reapondfasg to a
mixture of two toxicants which evoke
!ndividv»! respoewaa of Ft and Pa. then
(IV-S)
(IV-93
for this form of joint aettas have been
given by Msckstt and Hewlett (1@€8).
tare
i end do not allow for the1
maaswemeats of uyaergsstic a?
' toxicant interactioiis for mixtures of two
compotmda, Fismsy (1SQZ} proposed the
foUowing msdiBe&Mois of Equation 1V~4
Y-a, ^b lag (fe 4-pfe+K W&r^-t-fe tog 2
(TiMS)
where &i. b, fe, p ausd 2 are ds&ted as
befora amd K ie tfas ess«ffi«aeaS of
indicates ^ratagonisos. and a value of .
zero corresponds to dos@ ffiddi&on M in
Equation IV-4. Like oth«r prap0rad
modiBcatifMg of dose addition (Hewlett,
1989), the equation assumes a consistent
interaction thraoghost the entire rasigs
of praportiona of individual components.
To account fcrsBeia asymmetric
of iatcmetiraa as tfcass obsiafvad by
to
teg (?,-
OV-10)
in which K(p£5&)fte is divided into two
componeats, Kjf^pf.&j6-5 aad KB^(pft&
&*. Since K, and Ks natd not have- the
same ssga. appaiwii asstEccaa of
be estimated. Wfee0 K« aad SCs are «qaal
Equatkm SV-M ztsdwsea t@ Eqiaatiou IV-
9.
IV-10 requires that ths toxieity of
two
with assays of te tea-deity of th@
individaaS cessspoEents. Slace this
requires experiments with large
numb@re of animals, assds am&lysm have
been nsatricted for the most part to data
from acute bioassaye using bisects (e.g.,
Fiimey, 1S72) or aquatic, orgaraenns
(Ehirkio, 1S79J. Also, because of the
complexity of sxperimeffltai design and
the need for large mzmbara of animals,
neittosr &|Mat5oi8 XV-S nor Eqwatioss IV-
10 has bssz! gaaarKslizsd or applied to
edxtwss of laera ihan two toxicants.
medals to iradwia interactive tsnus hava
-------
m-7
No. @ / Wednesday, fanuaiy a IMS /'Notes
I17S
appropriate statistical tests far the
assumptios of addiiivity (Kara and Lisa.
1883; WafefBEdorf at aL. 1981).
measurements of tha extent of toxicant
latefasiSoita (§) can be sxpsssssd as tfes
ratio of observed relative risk to relative
risk predicted by sems form of
ratio of interact^ % classical
toxicology studies, S^l indicates no
interaction, S«l indicates synergism,
§
laterasticm is sptdemiaiogie studies. Am. J.
Loviae. RJ, 1S73. Pharmacology: drag
acMora.affid -reactions. Boston, MA: Little.
Bro«J33 aad Compsay, 412 p.
Murpby. SJJ. ises. Assessment of the
poteady for toads' interactions among
anvtaanmtal j!wUutaa£s.%j.- CL. Galii. S.D.
MurpJsy, esd It Psoktti, sds. The principlas
end tastheds ia saodsra toxicology.
Aiffistefdajs, Tfea Matte Sands: Ehewier/North
Hoilsnd Biosr.sdicaS Frais. <
NEC (Natiosial Eejaefjch Couasi!). ISSOa.
Drinking water and health, VoL 3.
Washington. DC: National Academy Press, p.
27-28.
NEC (Nafcicssal Raserach Co«neil),-iS80b.
Pdjsdplss of tesdcclopsai iutsmctions
associated with mtdtipls chemical exposures.
Washington, DO Natioaa! Academy Press, p.
204.
OSHA (Oecopstiisfflal Safety and Health
Administration). 1333. Gccsral ladnsiry
Standards, Subpart 2, Toxic and Hazardous
Substenscs, Cods of Federal Regulations.
40:19iaiOffiKd)(2)(i). Chapter XV!!—
Occupetionei Safely and Health
Administration, p. 667.
Pkckatt. &L. end P.S. Hewlett I94a
SSatisSeal aspects of the independent joint
action of poisions. Ann. Appl. Bioi. 35:347-
353.
Passat. U.C, CS. Weil snd CP.
Cerpeatsr. tS9& Tha toxicDlogtcal basis of
thrssfosld veiuss; & Tha experimantal
inhaJaaca of vapm mixtures by rats, with
notes open ths relationship bstweesi single
doae inhaledtsn end eiraglsj doss oral data.
Am. Inii Hyg. Assoc. |. 20:364-380.
Rothman. K, 197S. The estimation of
synergy or antagonism. Am. J. Epidemiol.
1G3(S):SC6-511.
Rothman. K. 197a Estimation versus
detection in the assessment of synergy. Am.).
EpidemioL 103{i;«-tlw
Rothmaa, 1C. S. Greenland, and A. Walter.
183a Concepts of interactioa.,Am. J.
Epidemiol. 112(4}:4e7-4m
Siemiatyski J« and D.C Thomas, ign.'
BiologicalTsodeLs end statistical interactions:
An example from multistage carinogenesis.
lat, }. EpidemioL 10(41:383-387.
Smyth. RF, CS. Weil ].S. West and CP.
€aipeaier. LESS-. An exploration of joint toxic
action: L Twenty-seven industrial cheraicaia
Intubated in rats in all possible pain.
ToxicoL AppL Phsmiacol. 14:340-347.
Smyth. HJ?., C.S. Weil ].S. West and CJP.
Carpenter. ISTa An exploration of joint toxic
action: !L Equitoxic versus equivoiume
mixtures. ToxicoL AppL Ph&rmacoL 17:499-
503.
Stara, J.F.. 0. Mukerjea. R. McGaughy. P.
Durkin, and M.L. Douraon. 1983. The current
use of studies on promoters and
cocarcinogens to quantitative risk
etsessiBsnt Envirois. Health Perspect. 50:359-
3SS.
U^. EPA. 138$. Proposed guidelines for
carcinogea risk assessment Office of Health
and Envsraamental AseesEment Carcinogen
Assessment Grctip. Draft
Veldstea^H. 1B5S. Sy-jiargism and
potentlation with spacia! reference to th@
-------
m-8
1178 • F«d«nl RraisKw / VoL 50, No. e / Wednesday. January 9. 1985 / Nottata
cocnbirntloo at itroctuial «icJeg»aj.
FtuewacoLJUv. 1338-387.
W*hradoi£I*R.Z«ntgrat«adCC. .
Brown. IBM. Optirad dwijra far the ncfysis
of teJtracth» tffiieti of two caidnoftsa or
Walter. SJX 1V& HM nttealiao «nd
f Bttrftwtabit risk talwmllh
an, ItadTJR. KoMbrf. 19Tt,
••Stfpfcstftv. *sdl otter awdteSs for
Wit&qr. PL lBtt.'i-
-------
-------
nx-io
433M
Fated Ragjgte? / Vol jg. Ng« J^g/ ._F^?7' Novan^eg^. l^£^Notos_
mvmotwcNML pKcnmcnosi
AGZKSY
Proposed Qufeteanea for Exposure
EnvireaiBzntal Protection
Agency (EPA).
ACTKX3 Proposed '"sidelfass for
Exposure Atssstsaitt-* and Request for
•UMiWCf: The U&Eisviroamsnta]
Protection Agsacy ia proposing
for Ebqjonen Asocsiment
(Gufekllaes). Tbesa GaJdelfats are
proposed fbffttsawlthiatfca policy scd
procedural framswork ptaowidtd fay the
various statutes which EPA administers.
data. We solicit public comment and
will take public comment into account in
revising mma Guidcliain. Tfccw
Guidelines will baxviiswed by the
Science Advisory Board in meetings
now tentatively scheduled for April
3885.
These propoesd Guidelines ware
developed as part of a broad guidelines
development program under tha
auspices of the Office cf Hosith end
Emrfroczantal Ast*sstBcnt (OHEA).
located In tha Aftacy'a Offlca of
Research and D*»»lopa«ni. ComsOTaat
with tba roJoof OHEA's Expense
Assassment Group (EAG) as the
Agency's senior health committee for
exposure assessment, the Guidelines
were developed by an Ageacy-wide
working group chaired by the Director of
BAG.
OATK Commoits meet b* postmarked
by January 22, 1983.
ADOMISSXK Couansnts may b* moiled '
or delivmd to: Dr. James W. Falco.
Expotute Aswsnaent Group (RD-esS),
Office of Health and Environmental
Aistfttaent, U.S. Eoviromnimtel
Protection Agency. 401 M Strest S.W,
Washington. DC 2D480.
Kit ttt
Dr. James W. Falco, Telephone: 202-475-
8909.
ttSVUDMHTJUIV HWOWHATWI*
Preliminary drafts of these Guidelines
were sent out for review to 15 scientists
and engineers hi the field of exposure
assessment within government,
universities in the United States and
abroad, and the private sector.
Comments received from these reviews,
generally favorable, were taken into
account in developing the Guidelines
proposed here.
In addition, as a result of the reviews.
four areas requiring further research
were identified aa follows;
A Iafjj9 msnb@r of mathematics!
models are used to estimate a wide
variety of parameters needed for
estimating exposures. Guidance in the
form of selection criteria axe needed to
ensure that the most appropriate
mathematical model is ueod for each
exposure parameter estimate.
(2) Development of Guidance for .
Analysis of Metabolism Data.
Guidance is needed to provida .
appropriate eon&ideratioffi of metabolism
data in the calculation of [whole body
dos« and in the extrapolation of whole
organism dosa from one species to
(3) Definition of the Relationship
Between Exposure Assasnment and
Epidemiology.
Guidance is needed to (insure that
• pertinent parameters of exposure are
qteesured in prospective opidemiologic
studies. Methods providing the beat
estimates of exposure for retrospective
and historical epidemiologic studies
must be defined. '
(4] Development of Methods to Relate
Exposures Measured by Personal
Monitoring to Source Contributions.
GuManes is needed to ostablish
msiffiaed by personal monitoring to
eoiEtroHabie eeurcas and to discriminate
among possible sources and between
background and anthropogenic sources.
It is the Agency's intent to revise the
Guidelines periodically to incorporate
the results obtained in the four research
areas defined above as they become
available.
la addition to the publication of the
• Guidelines, the Agency ako will provide
technical support documents that
contain detailed technical information
needed to implement the Guidelines.
Two of these technical reports entitled
"Development of Statistical Distribution
or Ranges of Standard Factors Used in .
Exposure Assessments" and
"Methodology for Characterization of
Uncertainty in Exposure Assessments"
are currently available. Technical
reports for the four new guideline areas
described above will be available at the
time of publication of the corresponding
guideline section. These technical
support documents will be revised
periodically to reflect improvements in
exposure assessment methods and new
information or exporiencai.
Support documents used hi the
preparation of these Guidelines as well
as comments received ar» available for
inspection and copying alt the Public
Information Reference Unit (202-382-
5928), EPA Headquartera ybrary. 401M
Street S.W., Washington. DC between
the hotve.of &00 sjn. and 4:30 p.m.
Bated: Nowabe? ft, 1984.
SHBasi FJ. Rssd
Administrator.
L tetrcductiaa
E> GmMofCuidelinss end Principla*
A. Expesism sad Dos®
H Daraeioe Pstfc to Deterausta Scope of (he
Asssssmsat
OL OcgsaJzatloa aad Contents of an
Exposure Aaaosamant
A. Overview
B. Dstailed Explanation of Outline
Stzmnw?
8. General Information
g. Sxposwv Pathways and Environmental
Fata
& Monitored or Eatimated Concentration
Levels
7. Exposed Population*
& Integrated Exposure Analysis
9. References
10. Appandexea
These Guidelines provide the Agency
with a general approach and framework
for carrying out human or norahumen
pollutants. HM Guidelines have been
developed to assist future assessment
activities and encourage improvement in
those EPA programs that require, or
could benefit from the use of exposure
assessments. The Guidelines are
procedural They should be followed to
the extent possible in instances where
exposure assessment is a required
element in the regulatory process or
where exposure assessments are carried
out on a discretionary basis by EPA
management to support regulatory or
programmatic decisions.
This doeuaaeai. by laying out a set of
questions to be considered m carrying
out an exporara assessment should hefy
avoid inadvertent mistakes of omission.
EPA recognizes that gaps in data will be
common, but the Guidelines will
nevertheless serve to assist in
organizing the data that are available.
including any new data developed as
part of the exposure assessment. It is
understood that exposure assessments
may be performed at many different
levels of detail depending on the scope
of the assessment. ;
These Guidelines should also promote
consistency among various exposure
asamsmeffit activities that are earned
out by tte Agency. Consistency with
respect to common physical, chemical.
and biological parameters, with respect
to assumptions about typical exposure
-------
III-ll
/ VoL 48.. No. 227 / Friday. Novemhef 23, 1884 / Notices
aeenmdtba route of ssjsosiise
gansraily topaets the overall exposura
and ihoold be considered la performing
expeneasss.
It is resogffltesd that tha mate
objective of aa ®jspsmssa assessmsat is
to provide ssliafels fata snd/«sr
assessment pressss sfeotald ba
coordinated with ths tadeity/effeEts
aasssssssat This desssBssi psewides •
commen approadk ts fsraat, which
& ^semea /&£& toDatseaua*Scope of
the Assessment
Ths Srst step hi preparing aa
exposure assessment should be the
cfeasascriptioa of the problem at hand
tss miaifflize effort by use of a narrowing
process. A deeisies logic pats that
describes this process is shown ia
Figure i. As illustrated in Flgers 1, t&e
preliminary assessment and the in-depth
assessment are two major phases in this
logkpath.
assessisg risk,
ActheAg@Q£
exposufs assss^ssate, Sfea Gaidsliaes
willbsravig
experience.
A. Exposure and Doss
. @sd
Fate, of tint Arassieaa
should commence by considering what
risk is under study and what law might
rega!ate.the exposure to tha agent
Within this framework, a preliminary
data base should be eaanmed &om
readiiy available edentiSe data and
exposure infcmatiras based on
mamafaetarsf, ymcassof. aadussr
praetieea, Next me most likely areas of
exposure {manufacuring. processing,
consumer, distribution, disposal,
ambient, water and food, etc.) should be
idssSffiesL Since a eomplats data search
feas Es4 fossa conducted. weO-identified
eatijaatss are used to fethsf narrow the
with enviram&eBtal and health effissts
In ooaaidedng tfea'sKpossffs of a
aub(3Gt to e hazardous .ageas.t, thsfa are
several related pnsesssez. The eoataet
beiwaaa the subject of eoasara aad te
agent may lead to the iataks of some of
the agent If absorption occurs, this
constitutes aa uptake (or an ataofbed
dose) which tbes may lead to health
effects. When bisiogsesl tissve or Sisid
chemical, espostwes can bs ssdmated
finra these data, foessass of a cheasii^l
in suds biolcgieal saaapl®s is ths meet
direct iodicgtioa that sat exposure has
•JHUMMftt im
11. auum *>« n> rmut
Data from this preuminary exposure
assessment can thsa be coupled with
toxisnty Mofsaation to perform a
risk analysis. As a result of
that either as in-depth exposufe
assessment is necessary or thst thers is
no asad for further sxpoaurs
contents of aa is-deptfe exposure
assessment are given in the following
section. •
Im afi€«E»b(iag the information base for
either a p?eltmmary assessment or a
more detailed assessment its adequacy
following eassMsrationa:
—Availability of information in every
area aeadedior as adequate
—-Quaatitetive end qualitative nates of
the data:
—Haliabiiity of infonoation;
—•OmitaMoEa oa the ability to assess
exposure.
C Uncertainty
Exposure assessments are based on
monitoring data, simulation model
parameter used in approximating
actual essposws emtsK&&3&&Qth de
gad sasuErotioiJS contain vsnytsig
the-aeeuraey of sspaaur® aesensmemts.
Aa evaluation of these uncertainties is
importaat whsa the azessament is the
basis for regulatory eEtiaa,
The oncertainty analyses psffanaed
will vary depending oa the scope of the
assessment the quantity and quality of
monitodng data eollsieted, and the type
and complexity of ssaihematicsd models
used. A diecessioa of the types «l
analysis used lor qeaatlfymg
fm me next section.
A Overview
A sogg^ted oufStaa for as expomsxe
assessment documsnt is given La Exhibit
1. The five major topics to be addreaead
within most @%pos%f@ gasessments ars-
as follows: SoaiFca{s); Exposure
Concentration Levels and Duration:
Exposed Pof>ulaii0!st(s); and Integrated
Exposure Analysis. These five topics are
appropriate for exposure assessments in
general, whether the assessments sis of
global, national, regional. local, site-
specific, workplace-related, or other
scope. The topics sse appropriate for
exposure assessments on new or
existing chemicals and radiossudidea.
-------
4830S
Federal
XZI-12
/ V«d. 49. No. 22? / Friday.
an also applicable to both single
media and multimedia aMMseownts.
Since exposure assamnsnts ara
performed at diffarcmt kvals of detail.
tb» exUot to which any at«m«aiant
contains items listtfd in Exhibit 1
dapeadi upon its scope. Hie outline is a
jold* to organize the data whaoaver
they are available.
& Detailed Explanation rfOutlina
l> Ebwcativa Smsmary
TIw "Bxeeativa Summary" should be
writtes to that it can stand on its own
a§ aaainietoa report. Its main focus
stocld b« OQ a aasadact dscEriptior. of
tha procedures used, sjttwnptioE*
employed, and summary tables or charts
of the results. A brief discussion of the
w.ffirtaintis* asaodated with the results
shodd bt included.
2. Introduction (Purpose and Scopa)
Thl* section should stats the intended
purpose of the exposure astesiment and
identify tha agent being investigated, lisa
types of sources and exposure routes
indoded. and the populations of
J.EXEEUTIVK SUMMARY
3. GENERAL INFORMATION
•.Identity
(1) Mo!itcsl*r formula and structure, CAS
somber. TSL nunbtr
(2) Description of technical grade*,
dotilimfnintr. additives
13) Olhcj ktaattfyins characteristics
b. C&eaictl aad FbT^cti Propuftia
4. SOURCES
a. CharactgrbaOoB of Redaction and
(21 IMitribctfon fat
c-Dtopdul
d. Seszmuy of Eavir^touatal RalcuKj
5. EXPOSURE PATHWAYS AND
ENVIRONMENTAL FATE
«.Trtw«poct tod Tnosforauttoii
b. SdtaUBoitioo of Prindp*! Pctbwayi. of
Hxposuiv
c. PredJctlns EmrironmenUl Distribution
8. MONITORED OR ESTIMATED • .'
CONCENTRATION LEVELS '
a. Swnawrjr of Monitoring Data
b. Estinuiticss of EDvirosuscnt&i
c. Comparison of Coocsntntion Estimates
with Monltorinx Data
7. EXPOSED POPULATIONS
m. Mnmra PopaktiODS (SIz*. Location, and
HabiU)
(1J Population »Ii» and chanctariattc*
(Z) Pojnilaacsj location
t3)PopDktioaIuibiU
b. NoohcmEa PopcUMccu (wbcve
•ppropdate)
{£} PQJmktfea locatioa
& INTEGRATED EXPOSURE ANALYSIS
s. Ce!cj?!atioa of Espoeuia
(1) IdsaUScatfan and djarsstttrizaHoa of
the esccsacd popuiatiosss ead critical
•kroaate of lie ecosyatsra
(2) Pathways of expoe^ure
b. Hasaa DocisEs'jy aad Monitering
e. DavoJopamtt of Espo»ufa Scaiiarioa and
& SwJaaBoa cf Uaeartaiaiy
& REFERENCES
3. GenersI Information
a. Ideality, Jl) Molecular fonnula and
structure, synonyms. Chemical Abstract
Service number. Toxic Substance List
number.
(2) Description of technical grades,
contaminants, additivss.
(3} Other identifying characteristics.
b> Chemical and Physical Properties.
This sabssctioa shoiiid provide a
euismary description of the chemical
and physical properties of the agent
Particular attention should be paid to
the features that would affect its
behavior in the environment. Examples
of factors to be included are molecular
weight. daBsdJjf, boiling point melting
point, vapor pressure, solubility, pKs>
easlScieiJta, and half-Jivs*.
The points at which a hazardous
substance is believed to enter the
environment should be described, along
with any known rates of entry. Points of
entry may fcs indoors sS well as
outdoors, and environments include
indoor settings such ss offices as well as
outdoor environments. A detailed
expciura aoxeaament should include a
study of souroa, production, uses,
deatrueiiQn/dispeiaal. and environmentsl
release of a subatance. The studies
should include a description of human
activities with respect to the nibatanee
and the environmental release!) resulting •
from thorn activities. It should account
for the controlled mass Sow of the
substance from creation to destruction
and provide estimates of environmental
releases at each step in this flow.
Seasonal variations in environmental
releases should also be examined. All
sources of the substances should be
accounted for with the sum of the uses.
destruction, and -the environmental
releases. The environmental releases
can be described in terms of geographic
and temmtral distribution and the
receiving anvironmental media, with the
form identified at the various release
points.
a. Characterization of Production and
Distribution. All sources of the
osGsistest with te scspa @f the
assssssasafc, stewid b® issfe-ded, such as
' imports, sfe-ckpilss, tnasportation.
acddental/incidsatai production as a
side reaction, and natural sources. The
scijrces sfaotsJ.d tea Iswcatsd, and activities
nee
should be idtjatiSsd.
b. Uses. Tha SMbiisa«a should be
traced from its sowras through various
uses (with tothe? follaw-up on the
products made I® dgienains the
as an
impurtiv], expwts, stockpile increases.
etc.
cantata an strafoiafdtoa of disposal sites
and deairaeifosa procsases. SHch as
wastes, tecteerattei of tha substance as
wasia, ,
deslnsctioss in a ma®wAasy vjsstawater
treatment piaat w destruction in the
process of using the end product.
Hazardous contaminants of the
substance may be included, and
products containing the swbstancs as a
contaminant may be followed from
disposal
the qua&iitigs of the substances released
to the various environmastsl media.
Sourcea ef rsJessa io the environment
include production, us&. distribution/
transport, natural sources, disposal, and
contammatiou @f other products.
Environmmlal rekmeas should be
Extremdy «klailad escponxe estimates
informatkra Stir saA 3:isaificsnt
emission fisaeesa tosataoH, amount of the
of tun® to esds eEwiroTKsiantal medium,
source, and itwa physical and chemical
form of ih« saSssteJEce being released.
associated with Site, emission estimates
should bs givasa. A detailed discussion
of prossdwss for estimating uncertainty
is presented in section ad.
5. Exposure Pathways and
Environxeental Fate
The exposu£@ pathways section
should oddrets® hs&f} & h@»rdous agent
moves fern &M gsme@ tss.the exposed
less detailed
aesesammi, bmad gfi-asralSzatieus on
b* msfcfes, fa &a abamace of data, e.g., for
new
-------
ZZE-13
•F@d®fal I ¥&l m. Ho. 22? •/ Friday. November 28, 1984 / Motless
43307
_
\
have to be predicted by analogy with
data frora other substesis®*. Fats
estimates may aiea be made by using
models and/or iSGisitosmg data and
laboratory-derived pseesm rat®
coefficients. At any level of detail.
certain pathways may fee judged
insignficiafti sod net pjjrausd farther.
involving eisvir®?*;. "saSal fats, ths
sources analysis de&ribsd fsrevieusli?
emissions to the sroiroaraefflt, amd
possibly the locations and form si the
emissions. The esvtesuriaantal pathways
and fats analysis follews tins (rafcstes>63
from its paint of IsMai^vis^Kjaeratol
release, through fee envisesraast t@ its
ultimate fata, It may result is an
estimation of tha geographic sad
temporal disidbutiQa of coaesntratkps
of the subeiancs in the various
contaminated envirosEaestei media.
a. Transport and tfomfcrmatietiL Ths
. substance, oass released te tha
environment may ba transported {eg,
convectsd downstream in water as OKI
suspended sedtosat'thrmigh fee
atmosphere, etc.) or physically
transformed (e.g., vslstiiissd, mailed,
absorbed/desofbsd, at&J; may undergo
as
bio4sgradati@!% of easy acstimsslate im
one or saors media. Iltua, the
environmental behavior of a sssbsJaasa
should be evaluated befoss expomnes
are assessed. Factors that should bs
addressed include:
water, raO, ead biolegigal n^dia? D»g3
it bioaesss'jjsls or bksdagsadsf Is it
.environmental media.
• Doe* the agsat rases with e&sr
compounds in &s essvireEsm-ssat?
, • Is there iatermedls transfer? W3i@i
are the mechantems for saJasmeiiis
transfer? What are the ratea of the
intermedia transfer or reaction •
mechanisms?
• How long might the agent remain in
each environmental medium? How does
its concentration change with time in
each medium?
• What are the products into which
the agent might degrade or change in ths
environment? Are soy of these
degradation products ecologically or
biologically harmful? What is ths
-environmental behavior of the harmM
products?
• Is a steady-state concentration
distribution in the enviramnent-or in
specific g#gms55to of ths environment
achieved? If not ess the aonsteady-
state distribution be described?
• Wfes4 ie the resultant distribution in
ths sa^iroamsnt—fc? diilerent media.
different types or forms of ths agent for
different gsographieal sraas. at different
times or seseona?
h, IcS&istificatian of Principal
Pathways tsfExposum. Ute prineipal
, tsgethsr with.
environmsntel tehavioral factors, to
detEnaiins the significant routsa of
and environmental exposure to
ths substance. Thus, by .listing the
important dssnseteriste of the
eaviramneatai release (esstering media,
emission rates, etc.) and the agent's
behavior (tetsirosdia trancfer,
• 5a follow ths
from its iisifM reslssea to its sabssquent
fate in the savimnasnt At sny point in
the environment human or
environmental expcsara may occur.
Pathways that result ia.
U&iWfefjte, Madala may ba vasd tg>
predict tmvironmentaS dlstributionc of
ehemieais. Msay modeling estimates of
environmental distribution of dtssaieais
are bassd m part, on moniSormg data. In
predieiifflg eotvironmeotal distributions
of cfessBleale, available monitormg data
stesteiss of tfee
agsaS to different emrira&rasatai media.
end its tim&depe&dence in specific
fssfraphieal kteatiosa (e.g.. river basins.
streesss, etc.).
& Monitored or Estimated Concentration
Levels
a. Summary of Monitoring Date.
Monitoring data era assd to identify
Felsasss (geurcs termsi.snd. in the
exposure pathways and fate
assisasassats, to quantitatively estimate
both release rates and environmental
conceatratioBs. Some examples of uses
of monitoring data ass: Sampling of
stacks of discharge pipes for emissions
to ths environment; testing of products
for chemical «r radionuclide content;
testing of products for chemical or
radioactive releases: sampling of
appropriate points within a
manufacturing plant to determine
Fslssssa horn, industrial processes or
praciicss; and sampling of solid waats
for djssssisai G? radiomuclida coKtsat.
These data shosjld bs charactaHsed as
to accuracy, precision, and
rsprssentativeneas. If actual
environmental monitoring data are
unavailable, concentrations can be
estimated by vamtss means, including
the use of f&t@ models (see previous
section) or. in the ease of new
chemicals, by analogy with existing
chemicals.
The analysis of monitoring data
should be considered a complement to
environmental pathway and fate
analysis'for the following reasons: For
most pollutants, particularly organic and
saw cIsKisseaJs, monitoring data are
n©t often yield relationships between
enviroamentai releases and
environmental concentration
distribution in media or geographic
locations tha£ hav« not bsss monitored:
analysis of momitoring data does not
provids iafosraiaticss on how and where
biota iafluesssa the enviroamentai
distribution of a pollutant: and
to individual sonnjea that EPA
can regulate. MoBstosmg data are,
?. a dkwgt eouras of isifofKEtioss
Gots£3islmti&ii&
enviromaental ns«dia that might
eontribaSs to significant exposures.
Generally, the envsranmemiai
drtfc«ttaoM
ths
may b® mqws®d, Future environmental
concsateaSiosM rasultissg from current or
past relsa&sa may also ba projected. In
some cases, both the temporal and
geographic distributions of the '
concentration may ba assessed.
Moreover, if the sggssS has natesi
sources, the ceatribiatioa of &ess \o
esswimffissBaatel sotscwatradaES may bs
relevant Thsss "background"
the
toxic eJfssSs sh&w m threshold or
svalsiaSed % an analysis of ths
-------
xn-i4
463QS
Reglitef / VaL 48. No.. 22? / Friday. November 23. a@S4 /_Notiggg_
uncertainty dtba model paxarastarz
and inpot variabtee.- Wfaca tha satimatm
of ibe enviroGicsiitsl craostrations arc
based oo mattutcMtfeil raad«!s,.tha
modal results should b« compared to
availabls mooitarfsg data, am any
significant dtetpanditi saotaM be
discossid. Reliable, analyilsally-
dttesniBad vakcs sboaM be ghras •
pCTcadttsst over Mttaatad values
whenever aJgniSe?'^ **iso«2iaitdes are
7. Exposed Fofra!atiQC3
Populations selected fee study may be
dona a priori, bet fretpsantly tha
population* will b* idsatfflnd as a recall
of the touice* aad let* stadtas, Praia as
analysis of tha distribution of th* agant,
populations convacted acd
tubpopulaticm (La* collections of
subject*} at potentially high axpiosura
can b* identified, which will then form
the basis for the popelaSJnns studied.
Subpopulationa of high sensitivity, such
as pregnant women. infanta, chronisslly
ill, ate. may ba studied separately.
In many cases, exposed populations
can ba described only generally. In some
cases, however, more speciSs
information may ba aveilsbla on matters
.each as tha followiEg:
«. /Sanaa Pupulattoio. (1) Populaticn
*£s» and chsnxls?i2t!c3 (e&, trends.
MX/OSK distribution)
(2) Population location
(3) Population habits— transportation
habit*, eating habits, recreaticcal habits.
workplaca habits, product use habits,
ate.
b. Nonhuman Populations (where
appropriate). (1) Population aisa and
ckantctariitica (eg, spcdas, trends)
(2) Population location
(3) Population habits
Ctnsus and other survey data may be
used to identify and decsriba tha
population expoecd to varkras •
contaminated enviroamsatal mgdia.
Depending on the chanctedstiei of
available toxicologies! data, it may be
appropriate to describe tha exposed
population by other characteristics such
as species, race-age-sex distribution,
and health status.
8. Integrated Exposure Analysis
The integrated exposure analysis
combines the estimation of
environmental concentrations (sources
and fate information)' with the
description of the exposed population to
yield exposure profiles. Data should be
provided on the size of the exposed
populations; duration, frequency, and
intensity of exposure: and routes of
exposure. Exposures should be related
to source*.
F@r raora dstsilsd a«E8« smaats, tha
£sfeHst$si ffiavireazseate! earassateattas
sbsnH ba eoscidorad in eonJuB^tion
with &a geographic distribution of ths
humaa aed esvfooamenial populations.
Ths b@hxvterai aod biological
chajsctsjistfes of the exposed
popnlatiffing should be soiiEidered and
tfca exposiCBS of populatsKas to parimss
esaceatra&oa profiles shcuSd be
«9t!mated.T&9 results can ba prsseoted
in tabular or graphic fesis, and ea
•ttttmate of tha u&certain^ aosocaated
with them should be provided,
a. Calculations afSxponurs* Tha
cufea/Gfeai ofztfpsiurs involves two
am/of aspects:
(1) MsatiSeatioa of the Exposed
Population and Critical ElccoBssts of tha
Ecosystem
i are
trations also should give the
gBOgrahlc@l -r^aaa ejad enviroamental
madia contaminated. The stated purpose
o&tha assessment should have
prsssrifoed the humoia and
environmental subjects for which
exposures are to be calculated. If the
subjects are not listed, thsi contaminated
geograpoisal areas and environmental
media can be evaluated to determine
subject populations. Tho dsgras of detail
to ba usad in defimag the exposed
pspaiifiaa distribntioa depends on tha
ccEct'steaJioa gradteat over geographic
areas,
(2) IdsaUBcatiera of patliways of
"exposure.
{&} IdantiBcation and description of
the routes by which ths substances
travel from production sits, through
uses, through environmental releases/
sources, through transport and fate
prccessea, to ths target population.
(b) Quantitative estimates of the
amounts of the chemical following each
exposure-pathway. Such nstimates allow
the various pathways to b« pat ia tho
perspective of relative impcrtancs.
From the geogrpabic and tempral
distribution of environmental
concentrations, the exposed population,
the behavioral characteriotics, and the
critical elements of the ecosystem.
exposure distributions can be estimated.
The results of exposure calculation
should be presented in a format that is
consistent with the requirements of the
dose-response functions which may
later be used in a risk assessment For
example, when health risks caused by
exposure over extended durations are
considered, average daily exposure over
th°> ^'-ratfosi of exposure usually is
calculated, When lifetime risks are
considered, average daily exposure over
a lifetime usually is calculated. In
contrast, when health risks caused by
exposures over short durations are
Many
to
assessments ess b@sed
axperara pmaa, xns ranga of
sibJa exfjfflsaraa is usually divided
into iaten'als, and tha exposures within
each iaterrai am sossated, The resaslts
Tha pcspffiktta rsidding in a. specific
gaegfapMs ajsa may fe® exposed to a
aufcstaiE'Es tern several exposuire routes.
For esefe exposure routs, exposure of
{Estivideai? izs these populations may be
f snramiag the contribution
expSMfe route, the relative amounts of
& BfsbeiajEB® sterbed is usually route
depeadsat. GraEeqciaEttly, total
absorbed sisss estimates must
for the» dMfarcissas. Bscaiiss EPA
ccatributioia to exposures from each
type of source being coaasdersd should
be displayed. Exposwre estimateai should
be presented for each significant
exposure route (Le,. those routes
consistent with te regulatory purpose),
and ths raralta flfecsald be tabulated in
h a imy fe,
and abeoTbed tiasa csa ba determinsd.
b. Hv-ssrn Bosisi-s&y' and Monitoring.
Bioiogicai swgmitoriEg of human body
Quids and ttenes for substancBs OF their
metabolites cms be used to estimate
current or past exposure to chemicals.
When analytical rasthcds are available,
chemicals tfeat hav@ been absorbed into
the body cam ba measured in body
tissue m& Ssssd. Suck measurements can
be ua@d to estJiaates exposure. However,
the a«ib@taK@a to which humans are
degrea to wMch they leava in the body
FurthssB^m. ftltfesagfe a compound may
be relatfvelf aasy to detect in body
tissue. Far s&am compounds, ettributimg
body bordana to ^specific environmental
releases may be difficult because of
limited ability to obtain environmental
monitoring data.
& Development of Exposure Scenarios
and Profiles. Depending on the scope of
the exposure assessment the totai
exposure may be fractionated into one
or more "exposure scenarios" to
facilitate qsiSHKiScaSioa, As am example.
Table 1 lists savsn very broad scenarios:
'
Transpcsstatifflia, Disposal, Food, Drinking
Water, essd Atabserai. For each of the
scenarioa. tha major topics necessary to
quantify saqsosasre issduds sousr.es,
-------
m-15
/..VoL 49, No.. 22? / Friday, November 23. 1984 / Notices
scenario rasy be aseessary fa? ths seeps sddrass the .exposure to applicators and assessment also -may consider other
ofsoiE8assss«!m®at*.F®r«?tarapl»,® populations ia the vicinity of the site. Aa scenarios. The more extensive and
pestteid® application expssw asspssarB assessment smsnd a comprehensive ths ssope, the morg
Imardsus'wasta site may foeus on the scenarios ara usually involved.
I. SXPSSM^ Asssssa«a«T'Rteeis Fras VAI^SUS 'EXPOSUKE SCENASSCS
fef*
Weatera.
estes
Csnai
teta e>
Ffesa ossss
fee tfesfcg
Woitara
-------
IZI-16
4S310
Federal Ragtste / VoL 43. No. 227 / Friday, November 23, 1984 / Notions
muBajsaci. ....... - * ..... . .. ...... tiirsaSMcciasf ^nimmmm-iaiamiia
that no strictly valid statistical
Inferences can be mad* beyond the
units actaally in the sample is one
aspect of tb« characterization of
unctrtaiaty. If infereaca procedures a»
impkaumttd. the assumption* upon
which these inferences ara hssad (e.g,
treatment of the sample as if it was a
shnpfa random sample. or aeaimjsMan of
an tmdcrfying modal) should be
stated and justified. The data
a methods ar d inheraat
BtattattenrftiM otta wxwM also ba
dli
An initial exposure assessment else
may be based upon limited data, such as
estimated ranges, for input variables for
: an exposure pceiliction model. Tne
expostas prodktioa awdel would b*
dcrivad from a pestniated exposure
scenario that describes the pathways
from sources to contact with population
members. If the data were only
sufficient to support estimates of the
ranges of tha input variables, tha
exposure aeaeaemeat might be limited to
a sensitivity analysis. The purpose of
the Mtssitivity analysis would be to
identify inflnrntial model input
variables and develop bounds on the
distribution of exposure. A sensitivity
analysis would estimate the range of
r*s that would result as
ml TTtftdrii input variables vtmm
* yajtiei with tfeg OtheT
pQf
mpot variables heM at fixed vaJtssa. fcg=,
their midrangtts. The ovemil minimyiq
and maximum possible exposures
tunzally would be estimated also. For as
exposure assessment of this type, the
uncertainty would be characterized by
describing the limitations of the duta
used to estimate plausible ranges of
model input variables and by discussing
jnstincatioa for the modal Justification
description- of tha exposure scanaria
choke of model input variables, and the
fimnttonal form of the mocleL Sensitivity
to tha model formnlatioa also can be
investigated by replicating the
sensitivity analysis for plausible
alternative models.
If the maximum possible exposure
estimated by the sensitivity analysis •
presented no significant health risk.
then might be no need to refine the
assessment If both the minimum and
maximum exposures presented a
potentially significant health risk, it
would be known that the exposure
scenario represented a significant health
problem without refining the
assessment. When the minimum
exposure estimate does not present a
potentially significant health risk and
maximum dose, then greater importance
is placed oa choosing a summary
parameter of th@ exposure distribution
(e.g_ the issaa or pe/centila) as the basis
for a regulatory decision. Refining tha
exponira assessment to estimate the
distribution of exposure permits
selection of any summary parameter
(minimum, maximum, mean, or
parc-sattla. etc.) as the basis for
regulatory decision.
Tha sensitivity analysis ftaa be
enhanced by computing thtt predicted-
axposusas mat result from all possible
feyrat variable combinations, If each
input variable baa only a Suite set of
possible values, th® set of «dl possible
combinetions of the input variables can
be formed, and ths predicted exposure
con ba computed uff each cxsmbinatiosi.
These exposure prediction!) can be used
to form a distribution of exposures by
counting the number of occurrences of
each exposure level or Iniarval of
exposures. This is equivalent to
estimating ths dintribiation of exposures
tSat results from treating all input
variable combinations as equally likely.
This procedure can also be applied by
discretizing continuous input variables
and representing them by equally-
spaced points. In the limit, as the equal
spaces become small and the number of
points becomes large, the distribution of
expeaare that results from counting
osssspisassii of exposure levels is
equivelsstt to estimating thsi distribution
of Rjspesares that jsmslta fasm
continuous
input variables with unifonn
diatribai'dans.on the estimated ranges.
This estimated distribution of exposure
values can be produced by the methods
of mathematical statistics or Monte
Carlo simulation. The Monte Carlo
method consists of randomly generating
input variate values and using these to
compute cczTSsponduig exposure levels,
generating an exposure distribution via
many iterations. Interpretation of
statistics based upon this exposure
distribution would be in terras of the
equally likely input variable .
combinations. For example, the 95th
psrcentile of this distribution would be
' tha exposure level excoeded by only 5%
of the exposures resulting from treating
all combinations of input variable
values as equally likely. Although this
distribution of exposures cannot be
interpreted as an estimate of the
population distribution (unless the input
variables actually are statistically
independent and uniformly distributed).
it provides additional information for
making regulatory decision*.
Characterization of uncertainty would
include a discussion of limitations of the
date and juatificatios for tha modal as
s. Sscsitivity
id alaa ba. io
by estimating the distribution of
ssms uuiftsrra input variable
distributioQg with plausible alternative
odels sad comparing the estimated
(3) Asmssmsnis Based Upt?n:
Subjective Estimates of Input Vacicbh
DisSribuHaiu. If & model has been •' ''
3ss»3 exposure as a
ftrncJte of one or mam input variables,
the methods of mathematical statistics
or Moats Carlo simulation can be used
to estimate the population distribution
of expsswi from an estimate of the joint
distribution of the modal input
variables. Ideally mode! input ifarisbbs
should b® rspreranted by empirically
validated probability distributioas. In
some cases, it may fee possible to
formulate an estimate of the joint
distribution of model input variables ,
from discacsiena with s^bjadt-matter
experts (&g^ via histograms for
statisticsUy-independeeit input
variables). The Estimated popalatisa
distribtitimi of exposure will be
equivalent t© the difltribution discussed
in section & d. (2) for equally likely
combinations of input variable values
only whera tha input variabla
ufeiform diatdbutioaa. Wtera
population members. The population
distribution of exposure can then be •••
estimated by computing the expected
exposure for each sampk member based
upon tha medal These expected
exposures can bs med to directly
compwSa csitfidsEaa interval estimates
for pereantiies of the exposure
-------
m-17
7 .
' No. .227 7 Friday. November -23. ,1884 Notices
distribution. Alternatively, the sample
survey data can ba used to compute
joint confidence iniarvai estimates for
percentiles of the input variable
distribution, which can then bs used to
generate confidence interval estimates
for pereentiles of th* exposure
distribution. In either case, ths interval
estimates for peraantites of the exposure
distribution are a-uscful quantitative
characterization of sr ^griainty.
Characterization of testriaiEty fe? the
thorough discussion of limitations of the
data and justification fo? the model used
to compute expected exposures. The
design of ths sample sarysy used to
produce the data basa should alse be
discussed. If a probability sample w«e
not used, the lack of a probability
sample would be aa additional source of
uncertainty. Any assumptions- ussd in
computing the confidence interval
estimates, such as independence of
model input variables, should be
explicitly stated aad justified.
Sensitivity to model formulation can be
investigated by estimating the
distribution of exposure for plausible
alternative models and comparing the
estimated percentilea, if sample survey
data have bean collected fo? ths
variables of the alternative.models.
Appropriate available data for exposure
should be used to validate the predicted
distribution-of exposure. If specific
probability distributions have been
presumed for any model input variables.
the data for these-variables should be
used to test for.goodness -.of. fit fcr.these
distributions.
(SJ Assessments Based Upon Data for
Exp&surs, A major reduction in the
tmssstalnty associated with an exposure
assessment can be achieved by directly
measuring the exposure for a sufficiently
large sample of members of the affected
population. This reduction in
uncertainty U achieved by eliminating
the us® of a model to predict exposure.
The measured exposure levels can be
used to directly estimate the population
distribution of exposure and .confidence
interval estimates for percentiles of the
exposure distribution. Direct confidence
Interval estimates also can be computed
for other characteristics of ths exposure
distribution, such as the mean exposure.
These confidence interval estimates
are then the primary characterization of
uncertainty for the exposure
assessment Limitations of the data and
design of the sample survey used to
ealk-ei tha data also should be
discussed. If the ssmpl® was not a
probability sample, this would again 'be
an additional-sourceof uncertainty.
(8J Summary. AiSuramsry of ths
'primary-methods recommended for
characterising uncertainty'-in exposure
assessments is presented in Table 2.
Virtually all exposure -assessments..
except those based upon measured
of population members, rely upon.a
model to predict exposure. The model
may be any mathematical function.
.simple or complex, that expresses an
individual's exposure as a function of
one .or more input variables. Whenever
a model that has not been validated is
used as the basis for an exposure
.assessment, the uncertainty associated
with the exposure assessment may be
substantial. Th@ primary
characterization of uncertainty is at
least partly qualitative in this case, i.e.,
it includes a description of ths
assumptions inherent in the'model and
their justification. Plausible alternative
models should be discussed. Sensitivity
of the exposure assessment to model
formulation can be investigated by
replicating the assessment for plausible
alternative models.
msaema tor • itflo sssa&a
. LMMfena ol
lot a
fnfifca eig, masn a
1. fesAfeita taS!OT»3 ssftnwi
SOT at !ft» BUJSKra tSuriajBcra.
2. G««3TOiS
-------
46332
• inc-ia
Federal Register / VoL 40. No. 227 / Friday, November 23. 1984 / Notices
The appendices may contain sncfa
items as memoranda ead letters that ate
notzsadily accessible, other tables of
monitoring data, detailed lists of
smiisioo sources, detailed tables of
exposures, process flow diagrams.
nutHynjjtfc-flt modri £onaulatioos« or
any other item Oat may be Deeded to
describe or docomeist the ejqmsote
-------
111-19
1SS4
Part VII
Environmental
Protection Agency
^^•r &'->
Propo«8d Quideffniea for Cardnogait RfsSc
Asa«»sm«flt; Request for Commants
-------
4623*
Fgd»ai
IXI-20
/ VoL 49. No. JB7 / Friday. November 23. 1984 / Noticss
AGENCY
b* followed iu developing analyses of
" Proposed Cfejfcfaiwa for CarctefKi
Alamos EBviroaniantil Protection
ACTXMI: Anpoeed Gaidetow for
C«K±aogta Risk Aractaamt and
KatJOBSt fcf
Guideline* for Cardn<>§ea Risk
t (Guidal&im). Theso
«a ptopcgad for on within
provided by thavariaQS statute that
EPA administer* to guide Agency •
analysis of cardnogenkity data. We
solicit public comment and will toka
pabllc commeat into account in revising
tfaeta Guidelines. Thssa Guidelines will
be xeviewed by tha Science Advisory
Board in meetingi now tentatively
scheduled for April 1985.
The** proposed Guidelines were
developed as part of a broad guidelines
development program under the
auspices of the Office of Health acd
Environmental Assessment (OHEA).
Iocs tad in tha Agency's Office of
Research and Devalopsicat ConKnint
with tha role of OHEA's Cardoogea
Awesinsant Group (CAGJaa the
Agency's senior health committee, for
cardnogenidty assessment, the
Guidelines wera developed by an
Agency-wide working group chaired by
the Chairman of CAG.
DATK Comments meat be postmarked
by January 22, 19BS.
ADOMESS: Comments may be mailed or
delivered to: Dr. Robert McGaughy.
Cardnogm Atscseneat Group (RD-
888); Office of Health and
Environmental Assessment, US.
Environmental Protection Agency, 401 M
Street SW, Washington. D.C. 2M3G.
pen fwmiEit mpmmxnott eem-Acr:
Dr. Robert McGaughy, Telephone: 202-
382-5852.
the first proposed revision of the 1978 •
Interim Procedures and Guideline* for
the Health Risk Assessment of
Suspected Carcinogens (Federal
Register 41SM02-2M05, 107BJ. This
revision incorporates concepts and
approaches to carcinogen assessment
that have been developed during the hist
eight years. Thesa proposed revised
Guidelines describe salient principles
for evaluating the nature and magnitude
of the cancer hazard from suspect
carcinogens and general framework to
Thee* Guidelines were sent to 38
scientists ia the field of cardnogenesis
from caive?dt?6», environmental groupc.
industry, labor, and governmental
agsadea. Wa have dijcidisd to delay
inoozporating suggestions from the 23
reviewm who submitted comments into
tha GuMolinoa published here until
is submitted during this public
period are raseivod.
• Refeeaces end supporting docomentc
Guidelines as well as comments
received ars availabla {bi; inspection
and copying at the Public Information '
Rsfewnet Unit (202-382-4S929). SPA
Headquarter* Ubrary. 401M Street SW...
Washington, DC between the hours of
&CO and 430p.m.
•Dated: Nownmbar 9,188*.
Ad-Siinisipatsf.
H. Hazard Ideatificstkm (Quniitativa Ride
Assessment)
A. Overview
a ElemtmtB of Hasard Ideatification
1. Phy«Jc«l-On>giical Properties «nd
Reat» tad Ptttenia of Expooiirs
4. Tajdeotogle Effects
ft. Laaf-Tesm Animal Studies
7. Human Studies
C. Weight of Evideoca
D. Guidaoc* for Quantitative AuMsunent
E. Summary and Ctmcliuioa
m. Dos^RsspsnsivB AescstnianJ, Exposure
Am-xxsoat. and Kiak dieneterieitiaa
.
3. CboieB of Msthsnatiatl Extrapolatiea
Model
3. Equivakxit Expoeas* UalU ABEOBS
Specie*
B. Exposure Ascnomaat
C Risk Charaetarisation
1. Opaosa Jw Numerical !Rlik EitiiniUes
2. Coacoszeat Expocuia i
3. Summary of Risk Characterization
IV. Appendix EPA aawificatlon Syatam for ,
Evideaca of Cartinogeocity From Human
Studies «nd From Animal Studies
V. Rofereacs* '
L Introductioa
This is the first revision of the 1978
Interim Procedures and Guideline* for
Health Risk Assessments of Suspected
Carcinogens (U.S. EPA, 1976; Albert et
aL. 1977). The impetus for this revision is
die >iced to incorporate into these
Guidelines the concepts and approaches
to carcinogen risk assessment that hays
been developed during the last eight
'years. The purpose of these Guidelines
is to promote quality and consistency of
carcinogen risk aasmsmsnts within the
EPA and to infosra those outside the
EPA about its approach to csrdnograt
risk asaetament These Guidelines
emphasisa the feraed btat essential
aspaete of nak assessment that are
needed by the esspatte in the various
diacipJiESS required (&g« toxicology,
pstfeetegy, phaffiaG®legy, and statistics)
r casetaogen araassraezt Guidamae is
of cardnsfpaesia is ia a state of rapid
advBEcasmat. and ©vei-ly specific
approaches may rapidly become
Yaesa Guidelines describe the general
en analysis of cardnogenis risk and
earns salient principles to be weed in
oatea and m^agaiteds of the cancer
hazard ftsam suspect cardnogenti.
A summary of ilss current stats of
and a statement of broad scientific
prindples of cardnogsn risk
assessment, which, was developed by
the Office of Science and Technology
Policy (OSTP, 1384), forms an important
basis for tags® Guidelines; the format of
thesa Gaidsiinaa to similar to that
proposed by the National Research
Coundi (NRG) of the National Academy
of Sdeffisw ia a report entitled "Rick
Assessment in the Federal Government"
(NRC.1883).
These Guidelines are to be used
within the policy framework already
provided by applicable EPA statutes
and do not alter such policies. These
Guidelines providegeneral directions
for analyzing and organizing available
data.- They do not imply that one kind of
data or another is a prerequisite for
regulatory strife to control, prohibit, or
allow the use of a cardnogea. The
•analysis of cardaogssie risks will be
carried cut indapeBdendy from
Gossaidemtiooa of fee sodoacosicmis .
'consequences of regulatory action.
Regulatory dedsionmaking involves
two components: Risk assessment and
risk managameat Risk assessment
defines the adverse health consequences
of exposure to toxic agents; risk
management combines the risk
assessment with the directives of the
enabling regulatory legislation, together
with aodoecoeomic, technical, political.
and other considerations, to reach a
decision as to whether or how much to
control future exposure'to the suspected
toxic agsnts,
Risk aextmrcrat includes one or more
of the foUowwfg components: hazard
identification, dose-response
-------
Fssteai / Vol. <& *jfe; jjg/ .^^'j^g"^.^*?8**^..
riak charactadsafesi (NRG. 1SS3J.
Hazard idaaMSestSsa is & qaaMtatlva
process of
exposure to aa agsaS hsd the pstessfSsI t©
inenus the incidence of cause?.
and benign tososs sss used is -.the
qualitatively aasr,-*at 4a question-of aL, tsm Maaiasi 1^0; Maeta! ead
IbensaaL
^USfe-FMo-At:. «vid«te8:of.'e«ciao|eaid4Fani.m«3r^
Traditionally, goaatitatfere riek
assessment has basa lisas! as sa
inshisiv® torn to dsesibs fiS eg pasts of.
doee°neapons@ -aaeassssisat, ascpaaws
Cssts? for T»fTD or partial SifsissBS eszpossjaa
toxidty, or if azrireal si
testing prodmastiaaofiiesponaaa by
ladfrggj mes^8si!iEi3!S:iljs? may te
-------
111-22
46296
Fadetal Register / VoL 49,' No. 227' /
tmrelated to effects at low*? doss should
b* dealt with on an individual basis.
< The mechanism of the cananoggnic
responses under condition* of the
experiment should be reviewed
canfuQy a* it relates to tha relevance of
tha evidence to human carcinogenic
risks (•*, th* oecawence of bladder
tenors in the presence of bladder stones
and Infection «it» sarcomas).
Interpretation ofanK^l studies is aided
by to* review of target organ toxidty
and oth«f effects (e#, dbangea in tha
teaum* and endocrine systems) that
may bo noted in ptechronic or other
toxlcclcgical stedies. Tims and does-
related changes in the incidence of
pmntopltstic ksteas may alao be
Helpful in intexpraiiiig animal studies.
Historical control data are often
whiable and ccaM be used along with
eonctBTent control data ia the
evaluation of carcinogenic responses.
Forth* evaloatfott of ran tenors, evea
small tame* rtsponsn* may be
significant compared to historical data.
In the case of tamora with relatively
high spontaneous rates, a response that
is significant with respect to the
experimental control group becomes
Questionable if tha historical control
data indicate that tha ^«p<»T"ti»n«al
control group had an nmtiniUy low
Afsnni that a» podtiva ia long- tena
^tfmyt experinrmU and also show
evidence of promoting or cocarcingenfc
activity in specialized tests should be
considered as complete carcinogens
unless there is evidence to the contrary.
Agents that show positive results in
special tests foe initiation, promotion, or
coc>rrfTtgiff'W*y «TUJ no indication of
tancr respcnsa in well-conducted and
well-designed long-tenn «»i™«l studies
should b« dealt with oa an individual
basis.
Thera are widely diverging scientific
views (O3TP. MS* Ward et aL lB79a;
MTBkTomatis, 1877i Natrition
Foundation. 1883) about tfaa validity of
mouse liver taaora when such tumors •
occur hi strain* with high spontaneous
background incidence and when they
constitute the only tumor response to an
agent These Guidelines take the
position that the mouse-liver-only tumor
response, when other conditions for a
classification of "sufficient" evidence in
animal studies are met, should be
considered as "sufficient" evidence of
cardnogenitity with the understanding
that this classification could be changed
to "limited" if warranted when a
number of factors such as the following
ant observed: The occurrence of tumors
only in the highest dose group and/or
only at the end of the study; no
substantial dose-related increase in the
proportion of turners that are malignant:
the occumnca of tumors that are
predominately benign, showing no
evidence of matastaaes or invasion: no
doss-related shortening of the time to
the appearance of tumors: negative or
inconclusive results from a spectrum of
short-tram tests for muteganic activity;
the occurrense of excess tumors only in
a single sex.
Positive carcinogenic responses in one
spsdes/sirain/sex ere not gOneraUy
negated by negative results in other
spedes/strain/isx. Replicate nsgative
studies that are essentially identical in
all other respects to a positive study •
may indicate that the positive results
ore spurious.
Evidence for carcinogenic action
should ba based on the observations of
statistically significant tumor responses
in specific organs or tissues.
Appropriate statistical analysis should
be performed on data from long-term
studies to help determine whether the
effects are treatment-related or possibly
due to chance. These should at least
include a statistical test for trend.
including appropriate correction for
differences in survival The weight to be
given to the level of statistical
significance (the p-value) and to other
available pieces of informatics is a
matter of overall scientific judgment A •
statistically significant excefls of tosiors
of ail typos in tfea aggregate, in the
absence of * statistically significant
increase of any individual tumor type
should be regarded as minimal evidence
of carcinogenic action unlesii there are
persuasive reasons to the contrary.
7. Human Studies
Epidsmiologic studies provide unique
information about the response of
humans who have-been exposed to
suspect carcinogens. Descriptive
epidemiologic studies are useful in
generating hypotheses and providing
supporting data, but can raroly be used
to make a causal inference. Analytical
epidemiologic studies of the case-control
or cohort variety, on the othar hand, are
especially useful in assessing risks to
exposed humans.
Criteria for the adequacy of
epidemiologic studies are well
recognized and include factors such as
the proper selection and
characterization of exposed and control
groups, the adequacy of duration and
quality of follow-up, the proper
identification and characterization of
confounding factors and bias, the
appropriate consideration of latency
effects, and the valid ascertainment of
the causes of morbidity and death.
The strength of the epidemiologies}
evidence for cardnogenicity depends on
fee magnitude, specificity, and
statistical significance of the response
sffid fecreassa rapidly with the number
'the
It shsaM iis »o>gntai that
epidesaioisgie studies ara inherently
capable of d@teefiisg ooly comparatively
large increases in t&s raktive risk of
cancsr. Negative $w«!ts feesm such
studies cannot prov@ the absence of
cardnogenie action: however, negative
results from a wall-designed and
conducted epidemiologic study that
contains Esabk i»:p«irar@ data can serve
to define uppw limits of risk which are
useful if animal evidence indicates thai
C. Wslght of Evident®
Evideaes of possible
in humane s&mes primarily from two
sources: LoEg-teraa animal teats-and
epidemidbgic iavsstigaMona. Results
from tfeecis studies are supplemented
with information from short-term tests,
pharmacokinetic studies, comparative
metabolism studies, structure-activity
relationships, and other relevant
toxicologie studies. Tha question of how
Judgment Judgments about &
-------
XH-23
/ VoL 48. No. 22? / Friday. November 2& 18ft> /
thecharaetsnsaStesaf t&sswsfall
weight of evidsssa fc? ssmasssafe
(animal human, and oths? gupptstlive
to Harness? Ckoop B-=Prei8ably
Cardnogeaie to Hammst C~-3?ossibly
CaKctoQ§e£iss to Humes® Group B—Mot
Qascifisble as to HSSESS
CareifflogcnicJJ^ sad Grasp ®=-?fo
Evidence of Csrtii&sgsiiieity for
Humans.
la addition, tha fallowing
modifications of tSa® IASC appsoads
have bean mad® for classifying hssmas
and animal studies. For Snussst atediess
should bs ikctamd into Iks dos@»
fsapaass assessment The appropriate
ajeshcd of extrapolation should be
factored M when the experimental route
inhumane,
Agents thai-ant judged ts be is the
Groups A arad 8 t-sfooUI fes regarded
tas risks Sross agaits far
GTSHJS C. spscsSeasHy tfeess afants that
ass at the bsEssdjsry of Groups C end 0.
weald bajadged oa a sa«a-by-cssa
and life-thfsatsaiajj fesiiga •
humans is inehided 5a the evalaatfess of
risks to humane. (2| A "a© svfdeacsw
category is addsd, TMs category
indicates that no assodatlGn was fosnd *
1 fes^^^^d risk of
cancer in wsE-eeadHGted, weU-d^iigB^.
independent analytical epidssaiolGgiG
studies. For animal studies: (1] As
and malignant tomors will bs
considered to provide sufUdeat
evidence of csfdn^snMt? if ths estte1
Use samraarf afeassld prsxssit ai! of the
key Ondisgs in cHof 4a« sactiems a? th«
qoaHSaiive ssasssmeal and te
fatsrpjettv® ratissiais that fonna the
basis for ths essctesios. Ihiceriainties
in the evidese® as wall as foetoss that
may aS&KJ the reievanea of the chronic
animal study ta humans shmiM be
coadusJea-sksuid
• unless tiss bssi^a tssisa sss nst
conafcierad to feivs fits potential fa
of the same mofpholofjie typa. (2| As
increased iseJdezres of bsai^s Snaors
alone as "limited" evidrazcis of
carcinogenMSy Is edifed. |3) Ifedar
ssmaat and Sisfc
ting the
:of a snbalassca
lectcd, evaiuatsd, and
productioeof
high spoB
•*Mnsitcd" if wssffset&d (a.g, &^a
widely
regardi^ the validity
tumors as an indie
human cardnogeaicity wfecT3 8Ms fe
only response obssavtal, «v,-5g la
replicated expesnsaata, sa ths ates3B3S
of other short-to^a evidencsj. (•§) A "no
evidence" category is-alss added. This
operational category would iaduda
substances for which there is no
increased inejdeoca of neoplasms to at
least two weil-designsd es«S weJi- .
conducted animal etudiea
in uptake. BWtBOoBsm.-aad orgaa
distribtition of carsta^essa, as well as
sits
are variabls.wife rsspsct to gssis.tis
undeHies te.qnantitatritt risk estimates.
.4. D&&e-&ssp&ii8ff. Aaaeasmeni
t. SelectioR -of Dsta
Asfe
ete,} ta -the ataSfefiea.cs
detemiiaed by ths quality of &@ data, its
rsisvsaca to human mode® of expesssns,
and oihe? technical details.
-------
Ill-:
48298
•• U.J
F«defal Rggfcte? /VoL49, No. 227 / Mday. Novmto
If available, estimates basad upon
human epldemiologk! data are praferrsd.
If adequate exposure data exist in a vrall-
detifoed and conducted negative
epidemlolDgic study, an upper-bound
aaifmat* of risk shookl b* used in
preference to higher risks estimated
from animal data. In tfaaabeESca of
human data, data from a spades that
responds moat like humans should be
used, if Information to this effect exists.
Where, fora given e^ont several
stadias are available -.Thlch may involve
different animal spsefss. strains, and
sexas, at several doMS and by different
mates of exposure, the following
approach to selecting the-data sets is
used. The tumor inddimca data are
separated according to organ site and
tamor type. All biologically and
statistically acceptable data sets are
presented. The range of the risk
estimates is identified with dcs regard
to biological rekvanca (particularly in
the case of animal studies) and
appropriateness of route of exposure.
Because it is possible that human
sensitivity is as high aa the most
sensitive responding animal species, in
.the absence of evidence to the
contrary, the biologically acceptable
data set from long-term animal studies
showing the greatest sensitivity should .
generally be given tha greatest
^fppTmK*, again with do* regard to
biological and statistical, considerations.
When tha exposure route in the •
species from which the doss-response
information is obtained differs from the
route occurring in environmental
exposures, uncertainties about the dose
delivered to the targot organs from
different exposure media should be
explicitly considered, and the
assumptions should be carefully stated.
When two at more significantly
elevated honor sites or types ere
observed in tha same study,
extrapolations may be conducted on
selected sites or types. Thasa selections
win be made on biological grounds. To
obtain a total estimate of carcinogenic
risk, animals with one or more tumor
sites or types showing significantly
elevated tumor incidence should be
pooled and used for extrapolation; if the
tumor sites or types are occurring
idependently, this procedure is the same
as summing the risks from the several
kinds of statistically significant tumors.
The pooled estimates will generally be
used in preference to risk estimates
based on single sites or types.
Benign tumors should generally be
combined with malignant tumors for risk
estimates unless the benign tumors are
not considered to have the potential to
progress to the associated malignancies
of thfteama morphologic type. However.
the comttiiffltica of the bsaijpj tumors to
the total risk should ba indicated.
2. Choice of Mathematical Extrapolatiosi
Medel
Since risks a4 low exposure levels
cannot be measured dirccilSy either by
. animal experiments or by .epidemiologSc
studies, a number of mathsmatical
models have been developed to
extrapolate from high to low dose.
However, different extrapolation models
may St the observed data reasonably
well but may lead to large differences in
the projected risk at low doses.
No single mathematical procedure is .
recognized aa the most appropriate for
low-dose extrapolation in
t When relevant
biological evidence on mechanism of
action exists, the models or procedures
employed should be consistent with the
evidence. However, when data and
information are limited, an to the usual
case given the high degree of
uncertainty associated with the
selection of a low-dose extrapolation
model, specific guidance en model
selection is necessary to provide* a
desirable degree of consistency in risk
assessments. The choice of low-dose
extrapolation models should be
consistent with current understanding of
not soialy sa goodness of 04 to-the
obsfwred tumor dataujnltkough
T^Hjjehaniaaiia of the carcSnogffinesis
process are largely unknown, at least
some elements of the process have been
elucidated, e.g* linearity of tumor
initiation. In further support of a linear
model, it has been shown that, if a
carcinogenic agent acts by accelerating
the same stages of tha carcinogenic
process that lead to the background
occurrence of cancer, the added effect of
the carcinogen at low dcas is virtually
linear. Thus, a model that is linear at
low dose is plausible.
The linearized multistage model
procedure for low-dose extrapolation
(U.S. EPA. 1880) is therefore
recommended in most cases unless there
is evidence on cardnogenesis
mechanisms or other biological evidence
that indicates the greater suitability of
an alternative extrapolation model, or
there is statistical or biological evidence
that exdudes the use of the linearized
multistage model.
It should be emphasized that the
linearized multistage model leads to a
plausible upper limit to the risk which is
consistent with some mechanisms of
csrcmogenesis. However,; such an
estimate does not necessarily give a
realistic prediction of the risk. In certain
cases, the linearized multistage model
caBMt be need sucssessiully with tha
obsarrod data aa, for example, when the
d»ta em Boamessatesic or flatten oat at
high dose®. La taesa casea it may be
"" " > tha
date an available, or when other
substrate! evidaaes on the rascfaraistic
extrapolation modal EBight b®
considered ousts appropriate on
biological grounds. Wfeea a differed
model is dsosaa, the risk assassmsnt
siurald dsaHy.diseass the nature and
cheica. la moat easss, considerable
t5a«rt®fej6f will ?ssiais eomcsraing
response at law deem; therefore, an
upper-limit risk estimate using tha
bepmanisd.
3. Equiwlaat Expoam IMta Among
Low-dose risk estimatss derived from
laboratory animal data extrapolated to
humans are complicated by a variety of
factors that differ aracsg species and
fasisra asts differences between humans
>b
pharmacoldntatie effscts sudi aa
metaboliBJra and exemtion patterns, and
the exposure wgisnea.
Tha usual approach for malcing
inSerspaciea comparisons has been to
use standardised scaling factors.
Commonly employed standardised
dosage smos include mg per kg body
weight per day, ppm in the diet or wates-,
mg per ma body surface area per day,
and mg per kg body wsight per lifetime.
In the absents of comparative
toxicolcgieal, physiological metabolic.
and pnazmacddn@tic data for a givem
suspect carcinogen, the extrapolation of
body weight to the 0.57 power is
considered to be appropriate.
B. Exposure Amsusment
In order to obtain a quantitative
estimate of the risk, the results of the
dose-response assessment must be
combined with an estimate of the
exposures to which the populations of
interest are likely to be subject. While
the reader is referred to the Proposed
Guidelines for Exposure Assessment
(U.S. EPA? 2934} for specific details, it is
important that tins cance? risk assessor
and te dedsioffl-maker have an
appradatkta of the impact of the
-------
IZZ-25
I VoL49, No. 227 / Friday,'November 23,1984 / Notices
482S9
as tfas overall canes? risk
pfasssa, ' ' ,' •' '
At pressnt tfess® Is no single 'approach
appropriate fcr all eases. On & ease-by-
caas basis, appropriate methods am
fleeted io matda ihs data ca head and
and WOPS* GSKB ansasmpttcms-vefsus a
monitoring data},
approximations, asd nncartainties need
to be dearly stated because, m asm®
iastasces, thasa will have a major effect
on ths risk assessment.
in general, the magnitude, duratieia,
and frequency of exposure provide
which ths organism is exposed. Thess
data are .generated from monitoring j
Information, modeling results, and/or
treatment of exposure shodd consider
tiie potential for exposure via ingestion.
inhalation, and darzaal penetration from
relevant sources of exposures. Where
feasible, an attempt should ba mads to
oasess .the dos@ to ths target organ.
eiJhar through expsstesstal evidssee .or
suggests expesrara regimsES, e.g» route
and dosing schedule, which are
substantially different from those used
in ths relevant animal studies. Unless
there is evideacs to the contrary in a
particular cass, the oimuiativs doa@
rscaived over a lifetime, expressed as
average daily sscposmia prorated ovss a
lifetime, ia'recorara&sidsd as tfes
appropriate measure of gxpasiiss te a
carcinogsB. That Is, ths @s§Bsmptiora is
mads that a high doss of a ejarcssacge®
received ova? a short period of time is
equivalent to a corespondfng low dose
spread ovs? a lifetime This approach
becomes more problematical as the
'exposures in question become more
intense but less frequent, especially
when there is evidence that the agent
has shown dose-rate effects.
An attempt should be made to assess
the level of uncertainty associated with
ths exposure assessment which is to be
used in a cancer risk assessment this
measure of uncertainty should be
included in the risk characterisation
(section OLC) in order to provide the
decision-maker with a dear
understanding of the impact of this
uncertainty on. any final quantitative
risk estimate.
ion.
' Typical- <
ppb infoed or water. m§/kg/dayrby
issaestioa s? ppm o? wg/m 3 in air.
b. Ths Dose Corrsspoading to a Given
Laval of Risk—Hsis -approach • -can be
nonlinear 'exteapolaticis modafs where
ths unit risk would-diHer at different
dose Isvels.
s. Individual and PapulationHisks—
Risk may be characterized either in
terms of the sxcssa individual lifetime
risks or the excess number of cancers
produced per year in ths exposed
population or both.
Irespective of the options chosen, the
degree of precision and accuracy in the
numerical risk estimates currently do
not permit more than one significant
in dsarastesisiag the risk due to
raEBajteat expasura te several •
earcdsogeas, the risks ars combiaad on
the basis of additivity tuslsas there is
specilie information to the contrary.
Interactions of :cocarcinogens,
promoters, and iaititatore with known
earanogess-should be considered on-a
cass-by-sase basis.
3. Suramaiy..of Risk. Characterization
Whichever method of preseatation/ia
chosan, it is .critical that the numerical
estimates not be allowed to stand alone,
ssparated/frojn the various assumptions
and MECBrtEinties- upon -which they are
based. The risk characterization should
cojitaia a diasKSBion and interpretation
of the numerical estimatss that affords
the risk manager some insight into the
degsse to which the quantitative
estimates are likely to reflect the true
magnitude of human risk, which
generally cannot be known with the
degree of quantitative accuracy
reflected in the numerical estimates.'.The
final risk estimate will .ba generally
rounded to one significant figurs-assd
will be coupled with the EPA
classification of the qualitative weight of
evideB€8. For example, a Ufetime
individual risk of 2X10~« resulting from
expoaun to a "possible human
carciaogsn" (Group C) should be
designated as:
1. ©ptioffis lor. Nttffisrical Risk Estimates
Depsadini on the needs of ths
iodlvidiial program dfScss, aumsrical
sstoates.can be presasstsd in one o?
m®m of the Mlswing'thf®3 ways.
SL Unit Hisk-^Under;aa assumption of.
iow-d@se linearity, ths unit cancerTisk is
the exsass lifetima risk.dus to -a
Tlsis bracketed designation of the
quaiitstiv@ svidenos should bs included
with all numerical risk estimates (Sse.,
unit risks, -which tar® risks at a specified
concsatfation,' or concentrations
.corresponding 'to -a given risk). Agsncy
notices. brieBflgs, and action
memofanda, frequently include
numerical:3stimates of carcinogenic risk.
ilt is recommended that whenever these
numerical sstimates- are used, the
qualitative weight-of-svidence
;c!p.asiHcatioa should also be included.
•IV. Appsnsfe-~£PA Claasifieation
Frozsa H
'SJMdlsa aad Fsnsa Aniinal
nsaa 1AKQ
for
dies in
Humans
'Evidence ofcarcinogenic ity from
human studies comes "from three main
sources:
1. Casa reports of individual cancer
patisnts;who were exposed to the
agent(s).
.2. 'Descriptive epidemiolcgic studies in
which the incidence of cancer in human
populations wasfosad to vary in space
or tims with exposure to the agent(s).
i3. Analytical epidemiologic (case-
l expostars to fee agent(s) was
found ta be associated with an
increased risk of cancer.
Three criteria must be met before a
causal association can be inferred
between •expoaurs and cancer in
•humans:
S. Thers is ao -identified bias which
•could explain tfee association.
'2.The possibility of confounding has
been considered and ruled out as
explaining ths association.
3. Tha association te unlikely to be
:dus to chaEiES.
to general, although a single study
may ;be indicative of a cause-effect
relationship, confidencs in inferring B
causal association is increased when
several independent studies are
concordant in showing the -association,
when ihe association is strong, when
there is a dose-response relationship, or
when a reduction in exposure, is
•followed by«a'reduction in the incidence
of .cancer.
'The, degrees of evidence for
carcinogsnicity* from studies in humans
••are categorised as:
* 1. Safficient evidence of
'Eor purpuss-of public health protection.
agents ascosiatstl with lifo-lhraatening
b-siiign tumonj ia humans are included in ihs
evaluation.
-------
,111-26 & , J '"• •
/ VoL 49, No. 22? / Friday, November 23, 1984 / Notices
csvdcnfanidty, which indicates that
~ lU a causal relationship betwasn
£ Halted evidence of carefraogenidty,
tack indicates that • causal
iastrpretattoa is credible, but that'
•JaniiilUs aatplaaattona. sedi aa
csjeatcavbias. or coofowcdi!-^, could not
adstruateJy be exdndocL
A. m«/?^mt«l» an
oscnt
M rites that
i evidemct, whkh
i cf two coodittona-
prevailed: (a) Them wen f rw pertinent
elate, or (b) Use aveilaMs studies, white
afcwrfng evidence of cuodatkn. did not
4. No crkUmca. which indicate! that
mm aoodatf on waa found between
sapcmfli and an increased risk ol
smrar in well-dtsigncd and waff-
eroductod independent analytical
*|*deinialegic studies.
5. No date, winch Indicates that date
an* not available.
RAmmsimntofEvfdmcafbf
Caedaogoaicity From Studies ia
EtpeiimantalAwmab
Thesa assessments am classified into
fire groups:
2. Sufficient evideaca* of
rarrfrtogmrilrity. which indicates that
^ of
TMtfrnunt and benign nmwaf; (a) fa
•rehipla sped** ox stains or (b) fa
•in&iptt experimtnts (pra£safaly with
different notes of adminlsttatlaa or
wing different dose levels); or (c) to an
annsual degree with regard to incidence.
site or type of tumor, or age at onset.
Additional evidence may be provided
by data on dose-responsa effects, aa
wil as information from short-term
tests or on chemical structure.
2. Limited evidence of auefaogmidty.
wfekh means that tha data ssggsst a
carcinogenic effect but an limited
because: (a) The studies involve a single
spedes, strain. or experiment; or (b) the
experiments are restricted by
inadequate dosage levels, inadequate
duration of exposure to the agent,
inadequate period of follow-up, poor
•{•Under Specific rtir-nmrtam^f, tUcfa >S
lb« production of neopUsnu that occur with
high (pontaaeotu background Incidence, the
«irfd«nc* may b« decnw»ed to "limited" if
warranted (o.j, thcr« «• widoljr diverging
•dtadfic views regarding the validity of tha
taooM liver tumor u «n indicator of potential
faemin cardnogcnicity when this is the only
respooM obicrved. even in replicated
experiments in the ebtence of thort-tenn or
M&er evidence).
{Benign and malignant tumors will be
rsmbtned unless the benign tumors are not
cotwjdared to have the potential to progress
to the associated malignancies of the sauna
Bwrphologictype.
survival, too fat* animals, or inadequate
reporting; or (c) aa increase in tha
incidence of benign turmors only.
3. Inadequate evidence, which
indicates that because of major
qualitative or quantitative limitations,
Use studies cannot be interpreted as
showing either the precair.ce or absence
of a eardncgenic effect
4. No evidence, which indicates that
there is no increased inddence of
neoplasms hi at least two wall-designed
and weB-ccndneted animal studies hi
different species.
5. No date, which indicates that date
are not available.
The categories "sufficient evidence"
aad "limited evidence" refer only to the .
strength of the experimental evidence
that these agenta(s] an carcinogenic
and not to the power of their
carcinogenic action.
d Categorization of Overall Evidence
Grqup A—Human Carcinogen
This category is used only when them
is suffident evidence from
epidemiologic studies to support a
causal association betwetm exposure to
the agenda} and cancer.
Group B—Probable Human Carcinogen
This category includes agents for
which the svidencs) of human
csrciiiQgeQicitjr &OIB epidinniologic
stadies raogea from ahaoiit "suffldent"
to "inadequate." To reflect this range.
the category is divided into higher
(Group Bl) and lower (Group B2)
degrees of evidence. Usually, category
Bl is reserved for agents for which then
is at least limited evidenos of
cardnogenidty to humano from
epidemiologic studies. In the absence of
adequate date hi humans, it is
reasonable, for practical purposes, to
regard agents for which tbera is
suffident evidence of cardnogenidty hi
animate aa if they presented a
carcinogenic risk to humane. Therefore.
agents for which then is inadequate
evidence from human studies and
suffident evidence form animal studies
would usually result in a classification
ofBZ.
In some cases, the known chemical or
physical properties of an agent and the
results from short-term tents allow its
transfer from Group B2 to Bl.
Group C—Possible Human Carcinogen
This category is used far agents with
limited evidence of cardnogenidty in
auliuafs in the absence of human date. It
includes a wide variety of evidence: (a)
Definitive malignant tumor response in a
single well-conducted experiment (b)
marginal tumor response in studies
having inadequate design or reporting,
(c) benign but sot malignant tumors with
aa agent showing no response in a
variety of shbrt-term taste for
mutagenicfty. and (d) marginal
response* fa a tisama known to have a
high and variable baiekgroimd rate.
fa some cases, ths known physical or
cehnu'cal properties of an agent and
results from short-term tests allow a
transfer front Group C to B3 or firora
Group D to C. .
Group D—Not Classified
This category is used fas ageat(s) with
inadequate animal evidence of
cardnogenidty.
Group B—No Evidenc*- of
Caroinoggnidty for Humana
This category is used for ageni(ej that
* show no evidence for cardnogenidty to
at least two adequate animal tests in
different spedes or fa both
epidemiologic and animal studies.
Albert RJL. Train. RJJ. and Andsraoa. S,
1897. Rationale developed by the
EaviKmmsatal Protection Agency for the
assessment of carcinogenic risks. I. NatL
Cancer but 53:1537-1541.
Feron, V.J. Cries, RC, Grfweraer. Jt, Pteto
R, Agflw, C. Althcffi I, Anrakg. OU
BbsMBUiai. R, Gabral. JJU», Defla Porta,
O. tto. H. Ktauaaria, G. Xraea, R, Mote,
U-Napalkov. NJ, Odaahima. S, Page,
MR, Sehramm. T> S6elnho£ D- Sugar. ]U
Tomans, U UeMeke. R. end Vouk. V. 1S80.
Basic requirements for long-tenn assays for
caraaagenidty. In; IjMJg-lsmn aod short-
tenn asaeeaing aaaaya for carcinogens: a
critical appraise! IARC Monograph*,
Supplement 2. Lyoa. France International
Ageacy for ReMerch oa Cancer, pp 21-83.
Interagsncy Regulatory Uaison Group (KLGJ.
1979. Scientific basis for identification of
potential carcinogens and estimation of
risks, f. NatL Cancer last, 93:245-297.
IntenttacipUnary Panel on Caidnogumjcity.
IBM. Criteria fat evidence of chemkai
carcinoganicity. Sdeaco 2S&682-6G7.
(ntematioaal Agency for Research
-------
Federal Register / VoL 4g, No. 227 / Friday, November- 23»
46301
managing the process. Wasbingtoa, O.C:
National Academy. Press.
National Toxicology Program. 1994. Bepsrt of
the Ad Hoe Panel on Chemical•'••
Carctaofeneais Testing and'Evaluatiosa of
the National Toxicology Program. Board of
Scientific Counselors, Available from: US.
Government Printing Office. Washington.
D.C. 19e*-421-iaZ:472fi.
> Nutrition Foundatfoe. 2883. Tbs relevance- of
carcinogenic r£k
to the Nutrition
Advisory Csmioittes
" itioo. Available
boos Nutrition FomtJatJoo. ISBN 0-03S368-
37-J5.
Office of Science and Technology Policy • ••
(OSTP). 3884. dsaiEicaJ carcinogens:
review of the teaoaee aod its associatad
. prindplea. Federal Register 4fc2ZSBS-2SS81.
Pate, R, Pike. M» Day. N» Gray. IU Lee. P-
Parisfe. S.. Peto, MUchard. 8, and
Wahrendoii J. 198a Guidelines for simpte.
seesiUve. significant tests for carcinogenic
effects in long-term animal experimoata. la:
• Monographs on the long-term and short-
term screening assays fa? carcinogens: a
. critical appraUaL 1ARC Monographs.
Supplement 2. Lyoa.Franca: Intemodonal
Agency for Research on Cancer, pp. 311-
42& . , '
Tomatie. L. 1877. The value of long-term
testing for the Implementation of primary
prevention. Ire Origins of human canesr.
Hiatt HH, Watson. JJJ, and Winsteia.
J.A, eds. Cold Spring Harbor Laboratory.
pp. 1338-13S7.
U3. Eavironmental Protection Agency (U.S.
EPA). 197S. Interim procedures and
guideiices for healtb risk ecanomic impact
assessments of suspected carcinogens.'
Federal Register n-314O2-Z14OS. ;
VA Environmental Protection Agency (U.S.
EPA). 1BUL Water qualify criterial
documen* availability. Federal Register
4&79318-7B379. .
VJS, Environmental Protection Agency (UA
' EPA). 1883a. Good laboratory practicna
standards—toxicology testing. Federal
Register 48^3822.
US. Environmental Protection Agency fU&
EPA). 19e3b. Hazard evaluations: humans
flyflj domestic *t*i™«i«- Subdivision F.
Available ftcjfc NTI& Springfield. VA. PB
US, Environmental Protection Agency (US.
EPA). 18B3& Health effects test guidelines.
Avaifcbl* from: NTIS Springfield. VA. PB
U.S. Environmental Protection -Agency (U.S.
EPA). l&fc.Prapoced guidelines for
xpoettnafaesnwit
UA Food «ad Drug Administratio
FDA). 1982. Toxicoiogical principles for the
safety as*e*smeat of direct food additives
and color additives used in food. Available
from: Bureau of Foods, US. Food and Drug
Administration.
Ward. liH. Griesemer, &A~ and Weisburgsr.
EJC 1979s. The mouse liver tumor as an
endpoint in cndnogenesis teats. Toxicol.
AppL PharmncoL 51^389-387.
Ward. ]M. Goodman. D.G.. Squire. !tA. Chu,
K.C, and Unhart. MS. WTSb. Neoplasiie
and nonneoplastic lesions in aging (C57BL/
8N x C3H/HeN)F, (B6C3F.) mice. }. NatL
Cancer lost 83^49-854.
ITU Doe. •VJBJW fltod 11-a-M: M5 q»|
-------
1TC-28
Friday
Nowtmbtr 23, 1984
Part IX
Environmental
Protection Agency
Proposed GukJettn«a for Mutagenletty
Risk Assessment; Reque*t for Comments
-------
m-2
Sagteter / Vol. 48, No. 227 / Friday, November 23, 1884 / Notes
SPA
smp^'
public es28ffl»t sad wOi taka public
3omm@at into seeofflat In revising Hhes
3ufddines. Ttea Guidelines will be
wars
s9SEsasHs4 (GHEA),
as
Guidelines wer@ developed by an
.Agency-wide working group chaired by
thssREAG-
by J®sassy 22, 1885.
Grasp (Ift-S^J, Office ofHeaifh and
, U.S.
EBviraapssial Protseasa Agency. 401 M
Sliest SW.. Washingtoa. DC 204m
Or. David Jacobson-Kram. Telephone:
202-332-733®.
comments received as a result of the
proposed guidelines fa? Mutagenicity
Risk Assessment, which was published
in the Fesfess! Register [45(221 ):74934-
74S88J on November 13, 1980. have been
addressed. Use guidelfesss published
here reflect the suggestions that were
provided during that initial comment
parted. A asw draft of tisasa Guidelines,
taking into account the easier public
comments, was recently sent for review
to approximately 14 scientists is the
field of chemical mutegsMtsis within
vensmssk imlwssil£» in the United
Cammeots rsceived Sraai these reviews,
§as38ffsllf favombk, were also takea
into account to developing the
CSsidoHssss psopssasl here. '
Rgfessjcss asd sappesttag docamaata
Gaidsiinss as well as comments
isesivsd ara available for ioipaetioii
es,d capfiag at to Publk MermaMoo
EafamEES Ussit (20^-332-5928), EPA
Headquarters Library, 4@i M SSnet, SW,
WssUogtoa. DC, betwaes the aoura of
fe00 a oa. and 4^0 pun.
Da««d: Hevambv 9.1084.
S Comments Received Ptam tfea F«d«aai
asgisSsa Ptiblication of the PKjpossjd 19SJ
sad Ageacy Raapoata* to
A. Ccasaasnis oa uw-Iatiaduciion
E Ceesaate Itelaaos to Hsritabls Genetic
G, Tasting Systems
O. Wesglit-of-Evidence Approach
£ Qasnd Jafeiva Aaeeueraent of Results
Guldsliass
J. Gcec^la I8skifag to Heritable
B> QtsolitoSiws AsassonsanS (Hazard
lizs^satismj
J, Mffitsgaaic Activity
Z, Chemical loterastiofls in the
C Qtumtitaiiva AMeasment
S. Risk Ghasaetsrizetioa
L Itstesdactfoa
On November 13. 196a the U3.
Eavkonmantsl Protection Agency (EPA)
pabiished purposed guidelines for
Mutagenicity Risk Assessment (i) and
isMdtsd comments on those guidelines.
Hie proposed guidelines of 1980
described the procedures that the
Agsasy wo»old follow to evaluate the
geaetic risks associated with the
exposure of humans to chemical
mutagens. These procedures
incorporated a weight-of-svidence
approach that considered the quality
and adequacy of all the available data
on a chemical substance in order to
make qtsalitative. and, where possible,
quantitative evaluations of mutagenic
potential, Tfe® Agency stated that
mutageffliidty risk assessments prepared
pursuant to the proposed guidelines
woiild be utilized within the
reqiiiremsHts and constraints of the
applies'®!® st@t&tes that the Agency
to arave «t regulatory
Th« cmsssst 'propossd Guidelines
address fes soawsoate sscsived in
Hies® GuidsMHS®, which adopt thS
propossl, SS&SSK sddltjaaal cliaages
'mads isreapoEs® to the comments end
zincs the tim@ of the proposal.
Use raszssat p£opas®d Gmdeliass
shanges Eiade in response to the
guidelines of 18SO. Thgaa changes dealt
me weight-of-sirfdaRee approach. This
section has hem CKpanded to deStss
"sumdeaf "suggestive,'0 sssd "limited"
evidence fe potestiei human germ-cell
mufaggoidSy asd to iadisde two
categodea of evidence, "sufficient" and
"suggestive" for chemical interaction
with the gonada. Also, in the
quantitative assessment section, the
domiaant skeletal and dominant
cataract tests have been added to the
list of systems for possible use in
estimating ths magnitude of genetic
made in the text for clarification.
A dreft of tbs Gtasmt proposed
Guidelines was submitted for review to
individuals from industry, educauonal
institutions. ejiivorasaantEl groups, and
other government agencies. These
reviews were useful in revising the
Guidelines.
The Agency hag not attempted to
provide in tha earroaf proposed
Guidelines a detailed discussion of tha
mechanisms of mustagesicity or of the
various test systems that are currently
in use to detect mutagenic potential.
Background infometioB on mutageaicity
. and mutagenic test systems is available
in "Identifying and Estimating the
Genetic Impact of Cksmieal
Environmental Mutagens.'* National
Academy of Sciences (NAS) Committee
on Chemical Environmental Mutagens
(2), as well as in other recent
publications^, 4].
For the information of the reviewer.
Chapter n discusses the comments that
were received in response to the
proposed guidelines of 1S3Q and the
Agency's responses to those coramants.
The current proposed Guidelines for
Mutagenicity Risk Assessment, for
which comments are currently invited,
are described io Chapter HL The
anticipates that, as methods for
mutagemdty risk assessment are
-------
m-30
/ VoL 49. No. 227 / Friday;
1884 / Notteag
4S315
, ami Bora hifef&uitisci becoiBS*
availabla In tha ara* of nrateguaidty,
nnrisioas to liitsa GuMdius may bs
IL ConnBneta Baoefcmd Ftasa d» ?«d«sl
•after Pcbfea&a of tfea Fsopaswl
1IM GaHeB-rs arf AtaBcy
As stated In t^&tradwtei, tha
correct GaMftoDi are being propostd to •
the infbtmattoQ of tka reviewer,, a
(CESJBAiy O* tftff PHt!?t]pS ffftJUHtmUffltf^
received la itfpasa to th« propowrf
iHi of 1889 and th» Agency
itspooies to tisow aonmaats axe
A total of 34 coamtntg ware reeaimd,
17 from mnEi&ietiffltti of regulated
duct*, eight from usoetethms. fimr-
itstimtiaa*. tad am •«& team * private
coxttuhiog laboratory and a gowOTmat
aftacy. Mmy rwpwissi noted that to*
and appropriate and praised the Agzasy
for initiating jroctdiBaa for sdentifis
evaiaatica ofmntngsnieity data. Other
eommantefa felt that the pmpcaed
guidelines wcra "ptttitere." Various
reesoos w«a given for this poritora: (1}
The Bm3»aiaiBa by which natations
occw aw not aeteitecid: (2) tha date
beats fop jnssgp amt»gissfcity tests ass
Bruited, and fateea &a tettt mn« net
been trsBdatci (3) the Agency tfecsld
wait until th* SPA Geca-Tox Program is
. completed; and (4) epsdemiologiestudies
T»H^Hff Uml ftfcinlb*<
Additionally, the commmt ignores th*
extensive body of data on ipcsiSc
chemical DNA ^^^««?*«, ntpair
proctsHs, and nnttatiooal expiasaifm
that enable descriptica of the mutmticaal
wocsts in «podSc pfeysiostasiffial terns;
(4.
With ragard tr? the saeoad commmt
tha Agsnesy tgre^s that the data bases
for maay mutagasieity teats ara Jisiitesfe
bowa«sr. tha Agsasj' does act agros that
tha validity .of a test is a function of tbs
aizc of tha data bass. VoUdity is tha
extent to whisib « test nassstirea ths
partiodar biologkal and paint of
iatKMt and ohooldi not m ctnifustd with
.jiaasitivity. fe« proportkas of feoswn
mntagens that asa poaitiwj is,£ systesj,',,
or spacifiCT'ty. tha.aropadion of
nomiitsgaG^ that are niEgativa. Hsncs. a
mutageoculs aseay is validated vyfasa Its
ability to detect a heritable genetic
cfcssaga is demonstrated.
- in response to tha third commaat, the •
Agoney does not beltevn it is Beeaaiary
to wait for eompletioa of the GSEC-TQK
Prograur before issuing guidelines for
evaluating mutagenidty data. Tfes
Agency acknowledges that future
sdantifie devdopments cm be expected
to affect the methods foi? the evaluation
of mutagenidty data. Such
developments may stem from phase U of
the Cess-Tax. Program (which focuses
on test applications) as well as from
othar collaborative activities in basic
end appliad raseardi. However, the
Agsasy fesEeve* that tfor corrent-
s» 83 written, can
With respect to the fourth comawnt.
the Ageacy does not agree that the
fates to identify a cheiDical as a
known human mutagen is juatificatic»
for sot proposing guidelines to evahiate
mutagenidty data. Despite the difficulty
In tmsriating chsngas in mutation rate
to altnfBtkHn is disease feequsaisy, tae.
MAS Committee oo Ghiimisei
EavisoozsEOtal Mirfageos hsa asseisded
that lite net a&est of an feasaae jn
mutatica rate is hanefnl because ahmoet .
ail nwtaats with any dafiactabls effact
A. Caaaaemtt en the Introduction
Many eomraenten OQ tha proposed
g«sidc£iijas of 1980 wmt critical of the
statement. "Sinsa the prospect of cnrinf
most heritable diseases caused by
amtagens in the near future is ua&keiy.
minimizing exposure to EK34agaaa i«
among the b««t available means to
protect against further deterioration of
the human gene pooL" At the psaaeat
time there is no direct eTideaca in
humans that heritable disease* are
h=J2S easssad by chemical mutagms. and
tasra 88 no evideaee of deterioration of
the geas pooL This ssatmse has bsen
deleted.
Several commmtgra ebfected to tfaa
statement. "Mutations are largely
recognized as being deioterions." and
pointed out thet many mutations are
silent orhave ao affeci. In the cuwsat
proposed Gaiideiinea, this sentenea has
beaa dusBgsd'is rsad, "It ia genaraily
ssssgaJsad tfaa: most nictations that are
are In earns
tha organSons
One commeuter requested an
gxplanatioa of how mutagenicity
guidelines would be adminiatersd snd
requested a statement indicating
requirements for genetic toxicology
testing in premarket manufacturing
noticas. The Agency believes that the
language in the current proiiosad
Guidelines deariy states that thay will
be used to assess risks associated with
human exposure to chemical mutageaa,
Requtements for genetic .toxicology
testing are the responsibility of the
appropriate Agency office.
B. Concept! Relating to Heritable
Caustic Risk
One commeuter: objected to tfes
definition of e mutagen becanses it was
not limited to stable and heritable
altemattons in the DNA. The Agency
agree* that the ultimate end point of
coacsra for the purpose of the cuzront
propooed Gaidaliaas is heritable and
itaMe imitation.^Por gene mutations,
heritabilHy is an obvious and naawiary
component steee aO teate need to detect
gene mutations actually detect mutant
cells or organisms that are descendants
of the treated cells. The same is not
always tree for certain cytogenetie md
points, such as chromatic! breaks, efe,
which may be detected hi the same ceS
generation in which they occur. Since
these latter end points provide
information relevant to heritable
mutation, they wQ! be consMered in sny
aautegenidty assessment As a jissniia.
the Agency fsals that the gBnaral
definition of a mntagen as used hi these
Guideline* is appropriate.
C JT«t«zflg Catena
One coEBmenter felt tfeat la-sst
cytogenatic end points that «se tsmtissbj
evaluated (e^, ehramoaoraB bfeaks.
micronudei) are not transmitted, and
thGfefoss,.afe not gormane to the sasae
of heritable mutation. The Agemcy
disagcoss. Although it is clear that ceils
that cany soeh aberrations generally do
not reproduce, otiter related abartaticnc
(Le« balanced tranBlocations,
inversionii, susall i
deSdenciea) are compatible with call
survival ia gmt calls and can be
transmitted. Additionally, there is no.
evideise* indicating that the mm-
transmissible aberrations occur by
-------
IS
111-31
Rsgssfear / Voi 48, No. 217 / Friday, November 23, 1984 / Notices
jversl ecaiasssjteES raqassfcsd that
Agsney establish jaJstesl criteria by
nteia that most bs asst for easfc
gves that the gsnefal prstosol* aid
:e-Tox Program as wall as other
.•ess proyids siaBeieai goidanes for
IB plasning to eossdaet muiagenidty
section required
iScatiom of the phrase, "positive
)0fflss in any two different point
ation test systems," because this
iss may be sabjest to various
jest to snisisteirps«tati«. Tlissefore.
atien tost gjntasu (one of which
zed marasaaliira eel's} or positive
xsasss in two different somatic
>genetic tests (one of which utilizes
nmalian calls), coupled with
rsetiois in both caea. Alternatively,
mammalian gene mutation assay
one msiarasJiaB cytsp&nstiea teat
sufSdent evidence ofgsm-ceil
•motion alss psovSdes saiflciejst
ienes of potential hmaas
:agesidiy. Tha dsssoateaSion of
itafala affects ind^esd ia mammalian
n cells ia by itself sufficient evidence
mutagenidty.
(any coramenters objected to the
erica that considers a chemical
agess a potential human germ-cell
.agen if there is "evidence for the
sence of the test substance and/or its
.abolites in mammaliaa gonadal
aos." First, they pointed out that the
sence of a chemical in the testis or
ry does not necessarily mean it has
cted with germ-cell ONA. Such
dies are generally performed with
iokbeled chemicals, and it is
sible that metabolism of the
npound could result ins incorporation
he radiolabel into iBsria.al cellular
iatsraeis with gam-call DNA. As a
lEsslsgsn internets in ths mammalia
gsaad will m Sfes demoiistrsition that an
ior
exchange (SCE), o? chromoiiomaS
absuaticES in genafaal culls. Suggestive
evidence will iadude advess gocadal
afFacte following acute, stsbchronic, or
dsronie toxidty tasting or advene
reproductive e^eets, such as dec?sasad
fertilization index, reduced sp$rm count
or abssnoal apenn morphology.
One eomiaenter suggested that the
Agency develop a seala of weighting
tests which would place more emphasis
on test systems more relevant to human
fosksgs, Ths Agency has explored the
possibility of developing such & seals
and has conduded that the assignment
of raxed values for each tast system
coidd be overly simplistic and might not
gllbw for th@ consideration of such
vadsbtes aa dsss range, route of
exposes, end asagmtode of respone.
assays and to germ cell rather than
somatic sail data, is raweatly the most
appropriate way to evaluate the
information from a variety of systems.
£ Quantitative Assessment of Results
Skwsrsl ccassaeatera expreassd the
opinion that it is not possible to
quantitatively express tSss risk of genetic
dissass from exposure to a dseuiical
snd-tharefors WB attempt should fea
snade'to do ESS, The Agency doss not
suggest that it $8 necessarily possible to
gsasKsSs a numerical estimate of the
genetic risk that will result from
exposure to any particular chemical. It
is wall-recognized and documented that
the mutational component of certain
categories of human genetic disease is
not known, Howevs?, mutsgenicity data
have been used to generate semi-
quantitative estimates of the impact of
ionizing radiation on genetic disease(5,
8]. The current proposed Guidelines
state the Agency's commitment to utilize
existing relevant mutagenicity data to
give some estimate of potential human
mutsgsmdty. AH sush estimates will
indude a careM deSfeeation of the
assumptions and uncertainties , "
associated with the assessment.
Maay comraentefa obfestgd to th® use
of "linsar or nonthreshoid ms$del@" for
that'linearity and the
preseara si" absanee of a threshold are
S2pa?ate is3«ss. T&s Agssney will strive
and will b® pr.sdsd by tha available data
Sa this s®Iacti«ss; H®we%-«?. i! is
fessiioE, M feass situations there is a
tlMC^etisal basis for a MSJSSF,
nonthrashold ejstrapalstioa provided
mapr germ-cell killing (and thus
' i c@ll
quantitative risk it is room appropriate
than on gene
mutatiGns, partlstslsiiy since many
diseases ess, bs more readily associated
with aa identifiable chromosome
abac£ra@lity. The Agency agrees that
asassiaJioKs between diseases and
specific efesmosoEsal changes can be
estimated. This concept is well
deraaseatsd and has been discussed at
length la the MAS rspori^J. However.
jEEKSatioiEs, asd swcb techniques have
e for effects o"
J. BSJCISMBB ths
by diifsrsaS dsssassals is known to be
variable, the Agency believes that it is
nfsssssary to psrforas estimates on all
end points.
One eommessSer objected to the
omission of ths dominant skeletal and
cataract Hsaistioa systems for
Agency rsasgmzes thst these dominant
mutation systems do have relevance in
the preparation of quantitative risk
assessmessj ald&g with specific-locus
test systems. The csjiresist proposed
Guidelines have fessa medi£i@d to
include both typ@s of testa.
A. Introduction
This section describes the procedures
that the U.S. Environmental Protection
Agency will follow in evaluating the
potential genetic risk associated with
htiKjsa exposure to existing industrial
chemicals and to pesticides. The central
purses® of the health risk assessment is
to provide a Judgment concerning the
weight of evidence that an agent is a
potential human nsKSagsn with respect
to transmitted gsaetig changes, and. if
s0. how great aa hapsst it is likely to
-------
UI-32
No. 227 / Friday, November 23, 198« / Notices
48317
decision making involves two
cocopomatKRIsk uecssciaat and risk
. Risk asstsammt estimate*
tha potential adverse hulth
coaseqotoses of exposure to toxic
ffKamt^aty; risk management combines
the risk aswssssat with tha directives
of tfaa enabling rafsktory lagiiktiae—
tofaUwr with eo^-^-iaoinic. technical.
political, and othar CTn»id««tica»-=-to
reach a dodcfon aa to whether or how
much to control future exposure to the
chBmntcals. The ism* of risk
manafemsot will not ba dealt with hi
thes* Guidelines
Risk aeaesffliSiit ia coosprisiHi of tha
following compoaflats: Hazard
Identification, dotw-respansa
assesiBBent axpoaura anossmant and
risk charactBrization{a}. Hasard
idcntificatioa IB tha qualitative risk
anassaent dealing with tha inherent.
taxidty of a chemical subatasee. Ths |
qualitative mutagenkity aaaesaaent
answers tha question of how likely an
agant Is to be a b*m^n matagen. The
three ramatntng components comprise
quantitative risk assessment which
provides a numerical estimate of the
public health conscquaacea of exposure
to an agsat Tha qusntistiva
smtassoicity risk asscssnst deals with
the qwtioa of haw much nmtational
damage la Hkely to be produetd by
expocura to a givm agent under'
particular expocura scenarios.
m a dose-responsa assessment the
relationship between the dose of a
chemical and the probability of
induction of an advena effect hi defined.
Tfo component fen-jafly entails an
extrapolation fioetlb* high gooea
acted in sots* epidsaie'cglc studio to
the low expocBm Isvda expecttd from
human contact with tha chemical fn tha
The expo*o» iuMMaaiaeat ideatifie*
populations expoicd to toxic dmieals.
describes then* compcdtica aztd siza,
and presents the types, nagnftndea,
frequencies, and durations of exposure
to the chemcials. This component is .
developed independently of the other
components of the mutaganicify
assewment and ia addressed in separate
Agency guldelin«(0J.
In risk characterization, the outputs of
the exposure assessment and the doea-
rcsponie assessment are combined to
estimate quantitatively the mulattos
risk, which is expressed as either
Climated Increase of generic disease per
generation or par lifetime, or the
fractional increase hi the assumed
background mutation rate of humans. In
each step of tha assessment the
strengths and weaknesm of the major
assumptions need to ba presented, and
tha nature and magnitude, of
uncertainties need to be characterised.
The proeedwis s*t forth in thew
Guidelines will eoaurs cosiaisieasy ia
the Agency's scientific risk a««szQ6!a£s
for nxatagsnd effecta. The nncessity for
a consistent approach fcj the eroiaktioa
of mutagsnis risk froia chiuaicial
sabetaiscn arisen from th$ an&oity
confteed upca the Ag@aey by ft nuraber
of statutes to requisite psteatial
mutagena. As appropfistit, ?Jj2s-3
Guidslinc3 will apply ts» atatssfcj
administsred by tha Agsx:^, fesli
.tha Pedonl Ihseetfcids. Fengftids. i
Rcdsatf cida Act; tfces Toxii; Ss&otsnces
Control Act; the Ciena A&'Acts tin
Federal Water Po&feE Csatf a! Ast; fea
Safe Drinking Water Act; the Resmsra
Conservation and fkots@mky Act: a.^ th®
Compeshensiva Envitonmtetal
Response, Compaisstio%|end Liabiity
Act Because eech statute fa
cdministeted by scparsfcs ^eee. a
conBiatant Agency-wide apsa-cach fo?
performing risk eaonsraeiiits is
desirable.
Ths mutagencity riek smaaemea.it
prepared pursuant to tfccsa Guidelines
will ba utilized within tha requireiaeats
and coflfitraiats of the applisabla
statetos to tirffto at rograate^ dodsimss
coxtcsiiiisg rcstigsssisitj/o YSis fttnsdsfdi
of tha eppUeafcls statatej and
regulatioaa may disrtate th-st xddit&mai
OCffllBIff'^a^HtlOSSS t6*&M tfe^ @^^§S^ffi|SSG SSSSa
social benefits associated with use of
the chemical substance) wiii coma into
play hi reaching apprepdate regulatory
Tha Agency ia conessnB^ with tha risk
asaodated with botiSi gEzra-ceil
mutations and somatic call mntatioeie.
Mutations ended in gseaceikeE®
inherited by totme geaerafteai smd-m&f
contzibnte to genatic dtaaW, wtereas
matatioas ocesn
may be UEpMeatsd ia the etidb^y-cf
aeveral dteasa states, indndfag cases?.
These Guidelinas. howeviK?. sea oaly
coocamod with genetic damage as it
relates to geim-cdl mutattats. The us®
'of muiageniQSy test resaits ia the
assessment of carcinogeaie risk ia
described hi the propcmad Guidsli^sa for
Carcinogen Risk AGsesesseatflS?.
As a result of tha progfeiiit ia me
control of infectious diseases, imareai^s
in average human life spaa, and belts?
procedures for identifying geastie
disorders, a considerable Karit&bie
ger.-Sc disease burden has been
recognized in the husasa pspuiation. It is
estimated that at least 10% of all human
disease ia related to spadfic geaeMc
states, such as abnosmsl campceaitte.
arranganent or dneage of igeaes @ad
chromosoiaes(£ & 21}. Sudi gunstis
diseenaa eara ked to stnictteai or
functional health impairments. These
ctmdfticiijfs may be expressed in utevtK at
As fcfoa of birth: or during infancy,
ckiidSicsmi. (fdaSefiSesss, or adult life;
they may bs chronic or acute in nature.
Aa a result they o?5ea have a severe
isapxct npen te affectad individuals
usid their famties in terma of physical •
stud raeata! siiSfesing and ecooomic
losses, and upon society in general.
which often basasiss rgsponsible for
institotieiiai care of severely affected
icdividiiais. Soasa examples of 'genatic
goraditkuas ais Down's asd Klinafelter's
Bjndso3!3i, «3ysfe Sbrosis, hemophilia,
giekls esil aassia, and echondroplastic
dwerEsra. Other commonly recognized
emditfera that ess likely to have, a
s, hypertension,
pyioris ste^saia, gkuc&ma, aHergies.
several typgg of as&cer, and mental
. retardation. These disorders are only a
. few of the thousands that are at least
EatiisaSI-an of tfca &ac!soa of human
genetic disease that results from new
mutation is difficult, although.ia certain
It ia ckar that reoimnf mutation ia
iopstest iss dcteEfsinisig ths incMesea
rfcsstaia geaffiMs CQudltiooi, such as
aberration
rare
dominaiit aad X-Kssked recessive
(e.^, aeiiondrnpiaaia and
}. For other single-factor
coisdittas (e.g» sickle-ceil anemia and
color h&:dse«!) sssd certain
pyioric
stcRttial, tit» oeratritetioii of new
.it is
ex^nssisi as® ia some ways dalstwieua
orphysioleigicat
Sirraia ef Gf^fflfeatf oa. Althoagli
BmtatieBe asw tte balding blocks for
&iicBja^ chenge of species, it
Is bs.Uffiired that iracmases i
nmtates rates above the spontaneous
level omutH l-Rad to an accumulation of
dsMmmm sEKfesiiossa in the hwmaa
papuiatfos snd. to a varying extent an
Lifa m Ger technological-society
.resniSs in expi^nm to many natural and
iyEtfesfe s?;esjlaala, Some have been
slM»a to tora mutagessic activity m
niSE3;aJi.*j3s sssid submssuB&Usn test
syttoiae, ssd feja may tows the
pstssliTi ts> igsrasaae genetic damage in
ealiJblMag ssiSs^fssis activity in various
-------
111-33
/ Fdday,
distributed amc&§ feeds, tobasse, drop,
feed additives, eesmatiss, industrial
, psatieides, eod eooaomsr
products. As OH? kaowleds* of genetics
aad disease etiology incfaasea, and
Ssimss beings Haps®v8t we ssaf bseoma
aw»ia of dKaai>ssi%-Jmdus©d feaman
§ass«Ie affects. Tha axiaat to ^jfelch
that will fee transmitted to fetes
isasfatissas Is ankaowsa at this Urns.
to
a outages is considered a djesaisai
substance as mixture of substances that
ess induce alterations ia the DNA of
either somatic 07 germinal cells. Tfes
rautsgenicity of physical agents (e.g..
radiations} is not addressed hers. There
are several mutagenic ead points of
concern to she Agency. Thesa Include
sai
feplieatioas.
s msaa, upcaons.
inversions, @od traaslocatisms, whereas
numerical abarrations are gains or
losses of whole cahiinoijomes (e.g^
irisomy, moraosomy) or sets of
chromosomes (haploidy, poiyploidy).
It is ceassivable that only one or a
few molffleales of aa active compound
may bet suiBetent to causa certain typaa
of heritable changes in DNA. Mutagenic
©W*3i?*$a n«ia
-------
IH-34
Fcdaal Register /VoL 49. No.,223 / Friday. November 23. 1984 / Notices
46319
Uu targit molecules for it least some
mechanisms of induced nondftuinctioii.
Other and points that proviae
information bearing on tot mutagenidty
of « chemical can bo detected by a
variety of test systems. Such tests
mason DNA damagu in euksryotic or
prokaryctic calls, unscheduled DNA
synthesis in mamanaUaa somatic and
fttm calls, mitotic recr nbtea'tion and
gene conversion La *«a*.i, and sister-
cfrro«TntttJ exchengs in i
somatic and germ cells. Results in these
aswiys are us*M becauw the Induction
of twsa and points often correlates
positively with the potential of a
chemical to indues mutations.
In general. for all thraa end points (Le..
point mutations and numerical and
structural aberrations) the Agency will
ptaca greater weight on tests conducted
in germ cells than in somatic cells, on
tests performed in vivo rather than fa
vitro, in eukaryotes rather than
prokaryotes, and in mammalian species
rather than in aubmammalian species.
Formal numerical weighting systems
have bean developed^); however, the
Agency has concluded that these do not
readily accommodate such variables as
dote range, route of exposure, and
majaituda of responss.
Th* Agency anticipates that from time
to time data from cfaestieally-expoMd
~" human beings will be available (e.g..
cytoaeaetic markers in peripheral
• lymphocytes). When posssible, the
Agency will use such data hi
conjunction with other studies for the
purpoea of performing risk assessments.
The test systems mentioned
previously are not the only ones that
will provide evidenca of muUgeairiiy or
related DNA effects. These systems are
enumerated merely to demonstrate the
= breadth of the available techniques for
characterizing mutagsnic hazards, and
to indicate the typsa of data that the
Ag«|cy will consider in its evaluation of
mutagenic potential of a chemical agent.
Moat; systems possess certain
limitations that must be taken into
account The selection and performance
of appropriate tests for -evaluating the
risks associated with human exposure to
any suspected mutagen will depend on
sound scientific judgment and
experience, and may necessitate
consultation with geneticists familiar
with the sensitivity and experimental
design of the test system in question. In
view of the rapid advances in test
methodology, the Agency expects that
both ths number and quality of the tools
for assessing genetic risk to human
beings will increasa with time. The
Agency will doialy monitor
developments in nmtagenitity
•valuation and will refine it- risk
assessment scheme as better test
systems become available.
R. Qualitative Aaasssmont (Hazard
Identification)
The assessment of potential human
germ-ceil mutagenic risk is & multiatap
process. The first step is aa analysis of
the evidence bearing on a chemical's
ability to induce mutagenic avents.
while the second step involves an
analysis of its ability to produce these
events in the mamntiiHmi.-yip»«i--All
relevant information is than integrated
into a weight-o£evidence scheme which
presents the strength of the information
bearing on the chemical's potential
ability to produce mutations in human
4jerm cells. For chemicals demonstrating
this potential, one may decide to
proceed with an evaluation of .the
quantitative'consequences of mutation
. following expected human-exposure.
« For hazard identification, it is clearly
desirable to have data from mammalian
germ-cell tests, such as the mouse
specific-locos test for point mutations
and the heritable translocatibn or germ-
cell cytogenetic tests for structural
chromosome aberrations.lt is
recognized, however, that in most
instances such data will not be
available, and alternative mians of
evaliistica will be Tequirsti.Tn such
mass iha Agency will evaluate the
evidence bearing on the agent's
mutagenic activity and the agent's
.ability to reach and interact with or
affect the mammalian gonadal target.
When evidence exists that an agent
possesses both these attributes, it is
reasonable to deduce that the agent is a
potential human germ-cell mutagen.
1. Mutagenic Activity
In evaluating chemicals for mutagenic
activity, a number of factors will be
considered: (1) Genetic end points (e#,
gene mutations, structural or numerical
chromosomal aberrations) distorted by
the test systems, (2) sensitivity and
predictive value of the test system* for
various classes of chemical compounds,
(3) number of different test systems used
for detecting each genetic end point, (4)
consistency of the results obtained in
different test systems and different
species, (5) Aspects of the dose-response
relationship, and (6) whether the tests
are conducted in accordance with
appropriate test protocols agreed upon
by experts in the field.
The array of mutagenidty testa
available will be reviewed within the
following qualitative perspective;
greater weight will be attributed to tests
conducted in germ cells than in somatic
ceils, to studies in mammalian ceils than
in tnibroammalian cells, and to studies in
•eukaryotic calls than in prokaryotic
cells. :
2. Chemical Interactions in the
Mammalian -Gonad
Evideacc for choEiiieai interaction in
th» mammalian gonad spans a range of
'different types of findings. Each
.chemical under 'consideration needs to
be extensively reviewed since this typa
..of evidence may be part of testing
exclusive of mutagenidty per se (e.g..
reproduction, mstabolism. and
mechanistic .investigations). Although it
is not possible to claasiry clearly each
•type of information that may be
available on a chemicaL two possible
groups are illustrated.
Sufficient evidence of chemical
interaction is given by the
demonstration that an -agejit interacts
with germ-cell DNA or other ctaromatin
constituents, or thai it induces such end
.points as unscheduled DNA synthesis.
sister-chromatid exchange, or
chromosomal aberrations in germmal
cells. Positive results in a mammalian
germ-cell mutation study also
demonstrate the action of the chemical
hi the gonadal target cells.
h. Suggastiva evidence will include
the finding of advers* gonada! effects
following acute, subchronic, or chronic
toxicity testing, or findings of adv«rae
ireproductiva effects, which are
consistent with interaction with germ
cells.
3. Weight-oif-Evidenca Determination
The evidenca for a chamical's ability
to produce mutations and to interact
with the germinal target are integrated
into a weight-of-«vide3cs judgrsant that
the agent may pose a hazard as a
potential human garm-cell mutagen. All
information bearing on the subject.
whether indicative of potential concern
ornot, must be evaluated. Whatever '
evidence may exist from humans must
also be factored into the assessment.
Information available will vary
greatly from chemical to chemical
'because 'there are many mutagenidty
test systems, and there has been no
systematic attempt to develop
information on all .chemicals of concern.
The responses noted for different tests
may also vary from chemical to
chemical since often :one does not find •
consistent positive or nagative results
across all tests. Chemicals :may show
positive effects for some end points in
some test systems, but negative
responses in others. Each review must
take into account the limitations in the
testing and in the types of responses
that may- exist
-------
43329
•XXX-35 - • /•''":
/ VoL 40, No. 227 / Friday. Movember 23. l@a§ / Notieas
categorization of Uss «raight of
a classification scheme is prasssated ts
fflusteBts, m a ssmpiifisd sssass, the
strength of the informatics bearing oss
rautageaidty (Table 1J. It fe not passiMa
'to ilusteats ai.p0teEfel etKsbfesfeJS of
, aad csasMssafete jsdjpaeEii
fa wfeisSz tasi» ®
taolageaie activity and evidence for chemical
taiasasncgB is tfas gonad. but the evidatsca is
ksa tfeas swiBsisaS. This eetegofy is ;
pffitostia% taigs and betarogaasous ia aattee
su^eiaatio
fe
ate
Svlssnsttiii evktees denotes a sittsaitoB ia
wt^j &s swidsajs ia HasiSsd to asfofsu&oa
s aetivity or to o-rideessi of
Table i sad diMSKst&i pssslotialy is
sections 1, 2, aad 3 ail fee
@sSs} piss snfScteaS svidcnos ihat the
isity. In additeis certain
c«as aad one stmem'aS tsbfamotom®
Biensgaslias ealla and
iiacaicali
wSth
SCS induction is ZEajasasMaa germ eeOs|
o? gaxn-csil tsats ia Mpsar eukaryotas
{&&. Drorapiiila tesSsJ may pravida a
DssigmatSan of evideaee e» limited does
not praduda Siss usa of such iafGisBa
to tst pmdties fotfwrtbss testog or to
riasit evideacs fcs? potential
.ggna-caH saistagefflidS^
include eases in wMds posiidvs
aliaagi
eH test Aim fe
geneml. suSdant svideaca s^sts whea
is conSnaed mntageaie activity to
« least two diffsraaft teat systsafe at
Isast BSSS of wlikdt is iss ^iSBEJHaSlss
Although dsSnitive proof of
naa&ratageaidiy is sot possible, it
sasEss appsopriats that a chemical conid
bs classified operationally as sot a
human gessa-cd! outages, if it givsa
negative'resfjoasas m those test systems
feat Scgstiisr fidfill the criteria (L&. all
tmSal faasaea garm-eell
rparfo
.Tset systems
soiB&is&t and limited that includes
cases hi which there is soma evidence
for mutageaic activity and for
interaction with germ coil&
Limited evidence !b? potential human
gaiai-oll uKJtaganidtjp esdaSs when .
. ovideaz® is availabk enSy fe
mntagenicity tests (otfeaar feaa
BsaamBaHan gessa fi®Kls) ^ only for
chemical interactions hs &e gonad. •
1. Sufficisnt en-idaEB* exists whsssa pcssitiva
nsjiMinses an damosstyated in:
a. at least 009 xa mva mammalian gens-cgil
mutatioa test, or
b. at leect two poict mntatioa tests (at ieast
one ia mammalian calls) plus sufficient
ovidsfflce that the cbemicai iutoracts with
mamsEaiiaa g«na caMa, OT
c laast two •tnteturai
•Takes into considaratioa tas extent
quality, and congistency of response* bearing
on an agent's ability to product mutageoic
events and to interact with in* mammaHnm
gonadal target. Nmmutegeaie teat responses
(e.g, SCS in gsrsE calls; may help to efevate
• capable of detecting week responses
(adequate statistical power) and should
ba spprapriats for the chemical or class
of ehaasieala under iavastigatioss.
MsgaSSif s svidsass of chemical
hiteragiio^ Is the gonad in the presence
of evidesea of mutagenic asfivity may
still signal SOTisg eoaosm is regard to
somatic effectsCl^. Other combinations
of relevant Msmstioa will most likely
require cas®4sy-ease evaluation. It may
also ba possible to operationally define
s cfeaassieal as not being a human germ-
csH smtsgea based en negative results
from other assays which provide
information about mutagenidty and/or
interaction with germ-cell chroraatin.
C Quantitative Assessment
Hie preceding section addressed
primarily the processes of hazard
identification. Le^ the determination of
whether a substance is a potential germ-
cell mutagea. Often, no further data will
be available, and judgments will need to
be based on mainly qualitative criteria.
For quantitative risk assessment, further
inforsaatiisra is required, namely,
dsfeaiiaatioa of the heritable effect per
itsii of esspoaure (dose-response) and the
relutesaMp between mutation rate and
dfesass incidence. Dose-response
inteaatte 5s corabiasd with
anticipated levds ssd patterns of
hussan sKpossire in csder to derive a
to obtaining dos@-
germinal siata iisas induced in miaet ;
mararaals. Several lest systems may ' '
provide such tefonnati0n, s.g., the
mease heritable frsrasloeatioa, doBiiroant
skeletal, dominant cataract and
) tests. Although the t
skeletal and cataract assays
dommsat mutatiung, the haritability of
ebserved effects has not been deaHy
obtained at exposure levels nree& highar
than those that will be experienced by
risk is obtained by exttapslaiiifig the
induced mutation frequency or the
observed pheiaotypic efiect downw&fd
to the approximate level of aatictpated
human exposure. •
Hie Agency will strive to use ihe most
appropriate extrapolation models for
risk analysis and will be guidad by the
available data and mechanistic
eoaMderatisns ia this selection.
However, it is anticipated that for tests
involving germ cells of whole mammals.
few dose points will bs available to
define dose-response functions. In these
situations certain theoretical
considerations will apply(r-0). For point
mutations, linear extrapolations with no
threshold may be used as a conservative
approjdiBation. provided the results'
allow one to nils out major germ-call
selection. For structural chromosome..
tranaiocations. linear extrapolation of
the experimental data is thought to
overestimate the risks at low levels of
exposure aad use of a multiple-hit model
is more appropriate. ,
The second experimental approach for
quantitative assessment of genetic risk
uses molecular doaimetry data from
intact mammals in conjunction with
mutagenidty and doaimetry data from
other validated test systems^). Tiss
intact mammal is used primarily for
relating the exposure level for a given
route of administration of a chemical to
germ-call dose. La., the level of mutagen-
DNA interactions. This information is
then used in conjunction with results
obtained from mtitagenicity test systems
in which the relationship between tha
induction of mutations and chemical
interactions with DNA can be derived.
-------
111-36
Federal Ragfctgr_/_Vol. 49. No. 227 /^Friday. November 23. 1984 / Notices 46321
Using mutagen-DNA interactions as the
"* common denominator,a relationship
can be constructed between mammalian
exposure and the induced mutation
frequency. The amount of DMA binding
Induced by a particular chemical agent
may often be determined at levels of
anticipated human exposure. This
approach is still experimental and its
application involves many unknowns.
such as possible difTarenaes between
mammaUan germ cells end cells of the
reference system with regard to types of
genetic damage Induced and magnitude
of repair.
For some mutagonic events. DMA may
not necessarily be the critical target
Interaction of chemicals with other
macromolecules, such as tubulin, which
!a involved in the separation of
chromosomes during nuclear division.
can lead to chromosomal
• nondisfunction. At present, general
approaches are not available for doss-
response assessments for these types of
mutations. Ongoing research should
provide the means to make future
assessments on chemicals causing
anauploidy.
S. Exposure Assessment
The exposure atimtmant identifies
populatou expocsd to toxic caaateals.
-^d*KsQ>*» their compodticn and size.
lutdpcesents the types, magnitudes,
, and durations of exposure
to the chemicals. This component is
developed Independently of the other
components of the mutagenicity
3, Risk CharactisrizatiQii
In performing mutagtoidty risk
asscssmmts, Itis impottant to consider
each gtzatie end point individually. For
example, although certain rfMMMteai
substances that interact with DMA may
ctus* both point and chroniosomsl
mulations, it Is expected that the ratio of
these events may differ for individual
chemicals »™j between doses for a
given chemical. Furthermore,
transmissible chromosomal aberrations
appear to be Indudble with higher
frequencies in maiotic and postmeiotic
germ-cell stages, which have a brief life
span, than In spermatogonlal stem cells,
which can accumulate genetic damage
throughout the reproductive life of an
Individual For these reasons, when data
ara available, the. Agency, to the best
extent possible, will assess risks
associated with all genetic end points.
Any risk-assessment should clearly
delineate the strengths and weaknesses
. of the data, the assumption!! made, the
. uncertainties in the methodology; and
the rationale used in reaching the
conclusions. e.g» similar or different •
routes of exposure and metabolic
differences between humanii and test
animals. When possible, quantitative
risk assessments should be expressed in
terms of the estimated increase of
genetic disease per generation or per
lifetime. or the fractional increase in -tha
assumed background spontaneous
mutation rate of humansfS). Examples of
quantitative risk estimates have been
published (6, 22}; these examples may be
of use in performing quantitative risk
assessments for mutageas, »
(2) US. Environmental Protection Agency.
198&MuUgeniciry:risk assessment proposed
guidelines. Federal Register 45 (221): 74984-
74988.
(2} Committee on Chemical Environmental
Mutagen*. 1982. Identifying and estimating
toe genetic impact of chemical environmental
mutzjpn*. Washington. DC: National
Academy Press.
(31 Committee 1 Final Report. 1983.
ScrsKiiag ateategy for chemicato that are
potential gsrm-eail muiagens in 'nMmimi«-
MuUtRsa. Sift 117-177.
M A complete reference of all Gene-Tox
publication* i* available' from tin* TSCA
Industry Assistance Office (TS-794), Office: of
Toxic Subateacae, U^. Enviromnental
Protection Ageacy. Washington. DC 20460.
(5) Cocsmittea on the Biological Effect* of
tonislng Radiatteo. isea The effects on
populations of expcsuM to km levels of
fcnizing radiation. National Academy of
Sd«nc«s. W«3hingtoo. CC: NBttHMJ
(6) United NatloM SdentUIc-Ckunmittw on
me EEbcts o£ Atomic Radiation. 1977.
SoBiees and effects of ianiztag radiation.
Report of the Gmcnl Asiembly^ 32nd
SesskBL. Suppteaant No. 4O(A/3Z/40), United
NaUoaa, New York.
(7} Ehling. UJi, D. Averback. EA. Cemtti.
I. Friedman. R Greta. A.C. Kolbye. and MX.
Mendnltohn. 1M3. Review of thti evidence for
the preteoce or absance of threshold* in the
Induction of geneticeffecti.by gcmotosic
chemical*. Mutat. Res. 123^81-341.
(4) Committee on the Inatitntional Mean*
for the AtseMment of Risks to Pjblic Health.
1963. Rltk atsetament in the Federal
government; managing the pncesa.
Commission on-life Science*. National
Research Council. Washington, DC National
Academy Preaa.
(9} UJ5. Environmental Protection Agency.
1S64. Proposed guideline* for expo*ure
aliessmenl. onica cf Health and
Environments! AMec*ntant
(10} U& Environmental Protcclion Agency.
' 1984. Proposed guidelines for carcinogen risk
assessment Office of Health, and
Environmental A**aument.
(«} Flamm. W.G. 1977. DHEW Report on
' approache* to datermiising the mutagenic
properdea of chemical*: risk to future
generations. Ji Environ. PathoL ToxicoL
•1:301-352.
• (12) McKuaicfc.Vj^l978.Mendeiian
inheritance in mam catalogs of autosomal
dominant, autecomalrecessive andx-linked
phenotype*. Baltimore. MD: Johns Hopkins
University Press.
(73) Crow. JJ^ and C. Deoniston. 1981. The
mutation component of geraetic damage.
Science 212:888-893.
(14} MusUova.1^ K.Micha!ova. and ].
Urban. 1979. Slater, chromatid exchanges and
chromosomal breakage in patient treated
with cytostah'cs. Mutat Res. ,67:28»-294.
(75) Strau**.;.GJt aud R.J. Albertini. 1979.
Enumeration of 6-thioguanine-resistant
peripheral blood lymphocytes in man as a
potential .test for somatic cell mutations
arising/n vivo. Mutat Res. 61:353-379.
(78): U.S. Environmental Protection Agency.
1983. Health effects teat guidelines. Office of
Toxic Substances. EPA S8S/8/B2-OQ1.
Available from: NTES.Sprijigfi.ld.VA.
(27) U3. Environmental Protection Agency.
November 24,1982,Pasticide* registration:
propoced data requirement!. Federal Register
47:53182-53203.
(IS) Parker. DJU and JJL Williamson. 1974.
Some radiation effects on legregadon in
Drowphila. Genetic* 78:163-171.
(7S] RusielL Utt. CS. Aaron. F. de Serres,
WJAGan«ro*o.ia.Kannan,M.Sh8lby.J.
•Springer, and P. Voytek. Evaluation of
existing mutageaidty bkwoaays for purposes
of genetic risk a*ac**mmt Mutat Res. in
.press.
(20J Ehrenberg U. 2. Moaitacchi, and S.
Oiterman-Golkar. len. Oosimatry of
geno toxic agentc and do*e-responia
rektton»hip* of their efiects, Mutat Res.
123:121-178.
(32) Lee, WJR. 1979. Dosimatry of chemical
mutagenc in aukaryote fermcell*. In: A.
Hollaender and' FJ. da Serres. eds. Chemical
mutagenr principles and mathods for their
detection. VoL 5. New York: Plenum Press,
Tip. 177-202.
(221 Ehling.'UJft. and A. Neuhauser. 1979.
Procarbazine-induced specific-locus
mutation* in male mice'.'Mutat-Res. 59:245-
250.
-------
s®; prsntoy pus -sisfea
40
-------
iday, November 23, 1S84 / Notices
ENVVIOfillfOTMLfnfOfHCTrON
AGCMCY
Itopowd Gukteftte* for tto rtoatn
Ageaey(EPA).
ACiwie Proposed Guidelines forth*
Health AsMmnunt of Suspect
Developmental Toxicants and Request
for Cocaasats. _ _
MMil«imTh*U.& Environmental -
ftotectico Agtocy is propoaiaf
Guidettttw for the Hsaltb, Assessment of
Suspect Developmental Toxicants
(GufcJtlinesJ. These Guidelines are
fuoporod for use within the policy and
procedural framework provided fay the
various statutes that EPA administers to
guide Agency analysis of developmental
taxJdry data. We solicit public comment
and will take public comment into
account in revising these Guidelines*
The Guidelines will be reviewed by the
Science Advisory Board in meetings
now tentatively scheduled for April -
Tflatd proposed Guidelines were
developed as part of a broad guidelines
development program under the
***pke* of th» Office of Health and
Enviroiantntal Assessment (OHEA).
located inthe Agency's Office of
Research and Development Consonant
with the role of OKEA's Reproductive
Effects Assessment Group (REAG) as
the Agency's senior health committee
for developmental taoddty assessment,
me Guidelines were developed by an
Afeacy-wkk working group chaired by
theREAG.
ZM7K Comments must be postmarked
by January 22, 1985.
ADonnsts: Comments may be mailed
or defrrextd to: Dr. Carole A. Klmmel,
Reproductive Effects Assessment Group
(RD-«ai}, Office of Health and
Environmental Assessment, U.S.
Environmental Protection Agency. 401 M
Street, SW;, Washington. DC 20460.
fott nmMXft tMramcAnoM COMTAGT:
Dr. Carole A. Kimmel telephone: 202-
382-7331. •
msemmaatrKKt «tromumon: A
preliminary draft of the Guidelines was
sent for review to approximately 20
scientists in the field of developmental
toxicology within government.
universities In the United States, and the
private sector. Comments received from
these reviewers, generally favorable,
were taken into account in developing
the Guidelines proposed here.
References end supporting documents
used in the preparation of those
Guidelines as well as comments
rscaived are available for inspection
end copying at the Public information
Reference Unit (202-382-6626}, EPA
Headquarters Library, 401M Street,
SW, Washington, DC, betweoa the
hours of tun aja. and 4^0 pja.
Data* Ncwwabara, M84.
Administrator.
CeoMs
L Introdoctian
ffl. Qualitative AMefsoMnt (Haznd
M«nMfleatiaoofD«»elopoB«Bt«l
A. Cooventfceal Oevelopmntal
TcocfeoJcfjr Protocols: End Points and
Their Interpretation
1. End P6ints,of.MatemalTaxicit?
Z. End Points of Dmrelapauntil Toxidty
, 3. Overall Evaluation of Maternal and
a Fnactional Teratology
C Short-Tena Tecting in Developmental
Toridty
I. In ViVnMaminiil^n TwitOJOgy Stltuq
2, Zn V/to Teratology Screen*
3. Application
E-HcmaaStodics
F. CaeiMrisaos o£&fobenlar Sbnctnn
G. WcrfghJ-af-Svidesict Detensktation
IV. Qossiitieathre AsaesiaMBt
'ft
C. Risk Characterisation
These Guidelines describe the •
procedures-that the U.S. Environmental
Protectioa Agency will follow ia
evaluating potential developmental
toxidty associated with human
exposure to environmental toxicants. In
the past, the Agency has sponsored
conferences and issued publications
which addressed issues related to such
, evaluations^ 2.3]. These publications
provided some of the 'scientific basis foe
these risk assessment Guidelines, and
testing guidelines have provided
protocols designed to determine the
potential of a test substance to induce
structural and/or other abnormalities 'hi
the developing conceptus. The Agency's
authority to regulate substance!) that
have the potential to interfere adversely
with human development is derived
from a number of statutes which are
implemented through multiple offices
within the Agency. Because many
different offices evaluate developmental
toxidty, theiB is a need for introagency
consistency hi the approach to aissess '
these types of effects. Hie procedures
described here will promote consistency
ia the Agency's assessment of
developmental toxis effects.
- Approximately 50% of-human
consepbises fail to reach term(& 4);
approximately 3& of newborn children
are found ta have oas or more
significant cangenital malformations at
end of the first
postnatal year, about 355 more are found
to have aertous developmental defects
(ft ••% It is estimated that 20% of human
congenital EtalibrmatiQEis are caused by
mutations, 10X are attributable to
known environmental factors, and the
remainder Transit &om unknown causes
NsaEarooa agents have bean shown to
be developmsiatai toxicants ia -animal
test gystemei&j. Several of them have
.elsoibeeQ showa-to'be .the .cause of
.advene developmental effects hi
, ,
busnUen. chlorobiphenyls,
diethylstiibestnil. ieotretinoin, organic
mercury, thalidomide. and vaiproic acid
(3,10.0.12). Expcistire to agents
affecting development generally results
in multiple manifestations
(malformation, functional impairment
altered growth, and/or lethality).
Therefore, asseantieat efforts should
encompass a wide anay of advene
developmental and points such as
spontaneous abortions, stillbirths,
malfoncaiktns, and othar adverse
fonctional physical changes that occur
postnatatty.
The developmental toxidty
asssssments prepared pursuant to these
Guidelines will be utilized Within the
requirements and constraints of the
appUcable statutes to arrive at
regulatory dedciaas iconceming
developmental tasddty. These
J provide a general format for
analyzing and orgaisMas the available
date for conducting risk assessments.
The Guidelines do not change any
standards tor dm type of data necessary
for regulator action. Moraover, risk
.assessmea} to just oaa component of the
regulatory process and defines the
advene health consequences of
exposure to a toxic agent The other
component, risk management, combines
risk assessment with the directives of
the enabling regulatory legislation
together with sodo-economic, technical,
political, and other considerations to
reach a decision as to whether or how
much to control future exposure to the
suspected toxic agent The issue of risk
management will not be addressed in
these Gaidelioea.
has deflnsd risk assesament as being
comprised of aoma or all of the following
-------
211-39
/ Vot «, 'No/227'/ Friday November 23. 1384 / Notea
'componants: hazard ideatifieatiem. doss*
raspoaas szaessmsat, exposus*
- - .&
general, tfaa process of assessing the rials.
of hmaaa daveiopme&tal tojddty may
be adapted to this fomst Hans&vw, dua
to special consideratio&s sza assessing
dev«lopia«Et«l texssit1^ which will fes
discesssd kter ia ttesa Cfeisfefes®, it is
not always apprr saA
tia
IL Defiiatlssaff
Hia Agancy DKS®gaizea> that &•«?&• ass-
differanca* in. thta u».'o£ teesa^ia Jha-
ftald of. davelapmaalal t
_ ' will be used.
Ds'stslopmentGl Toxicology*—The Said'
! with the inductio
tfcs time of puberty. The
vsiopmaratal
Em&syo&sxissty and Fstotosdcity^-
Am^: tods- «Soct oa- fes-csacaptae ap@-
i«8«ilt of ps«»stal ^^asurar the
distinguishing featei®S®t«w®s ths tema?
is the tfzsiad dariag wfelcfa tfeamaalt
oeoomdi T&a tasnse* a^ueesf ksa,
rowth.
- A
badjrw^gkJi BodfE waigbt may er may
ast ba -assGHspasiad % a dianga to
. BM>i'ha»i8gin«-
aad miHiSsstaiSons o£aliaiatiana or
maltestion is usually de&ned as a
to a«pmat
til®
el'ecf OB &nx«£raLo£ hsaM a* e.
variations
shies tEere esdsts a continuum of
responses &om the normal to the
extreme deviant There ia no generally
accepted classification of malformationa.
often used bus no Batter
indudes asaomali'ea, deformatioEja, and
aberratione.
TeadsamfeJ-
provide a
assftil for
ttaodd^c atodis®
ass-
>ats cpneeptu@ that may bs-peeduiaad hfi
as ttlsijp® wogostiss to, *nv*>?
growth, and function
the Srat three effscts are nssMaassasdte
the conventions! developmental Jojcieity
asldom evaluated ia routine
This ssetlora wiEdissuas the format and
analysis of «3ffiv®ffltional studlss as well
as th@ u@@ of data fbssa otissr typea of
atudtea, including foaetiocal stodisa,
, aad pharmacddaaiics.
Toxists/soy Protocols: End Points aad
The meat commonly used protocol for
involves the adBEimstraSioK of a teat
substanea to p^egEaaS aaimaie (i?.sas.Ey
sales, rats,. GKsafetoa) during, tins persod
find the
use asspoeuss'psdodS.of ose ta a-few
:ar
seaaitivlty Ibr induction of
spsd3c organs or organ systws^lS],
Fetuses alive at matemel saeriBfis ara
thoraugMy evaluated for eiteratiejiis ia
sitoiiidiach
IdB8%,
higB dosai wMdt producas some
(NQEL5.fesss*S3ffi&!
gf«SGgs. Ssi
fas
• The nesct tern- ssettteas dis
individual end paints of rastasssslSassds
dsvelopmeatal to^ldSy,.
svalustiora ofaS'dati£.shd'uding;tIie-
relative eifets-ef "expjsam on metei
aniusalkssssl tSaiFoSeprfc^i..
obs37v@d as indisatora of maismal
tcairaty are listed in Table 1. M^ternaf
-------
4SS28
in-40
Federal Register / VoL 49. No. 227 / Friday. November 23. 1984 / Notices
oortallty is an obvious «nd point of
maternal toxldty: however. a number of
other cad points eta be observed which
may ghre an.indlcatioa of the subtle
effects of the agent For example, in
weB-coadncted stadia* the end point
percent pregnant, iodise tes the general
tetiUty rate of tbaankial«todc used •
cod I* ea important indicate* of toxic
efiecta if treatment begins prior to
implantation. <
MbrUHty
BKc*BtEr«iB
(iachidsa «fl litters with
Treatasrt days (at least tat middk. and
. bat treajjBMiit days) Sacrifice day
Bogy W aj^hl Chii?ffi§
Thrccjhoei GattmtJoa
0urio§> h1 nil Ui nil nl (indnpln^ incrmfints of
time within treatment period)
FoeMnetmeot to sacrifice
CocrsctsdnurtanuU (body weight change
t gestation Bifntis gravid
Blarfna weight or Utt« weights*
uoifice)
Orjfta Weights (In cues of suspected tpcciSc
organ toxidty)
Abtohrte
RaUithre to body weight
Food and Water Consaaipi&m (whore
telcvxnf)
CBafcal S^pm (OB daya oftnuttBent aadat
•eoifiai)
fetidtae* of cUaical signs
Body weight end the change in body
weight are viewed collectively as
indicators of maternal toxicaty for most
tpedes. although these end points may
not be as tuwful in rabbits, because ..
body weight changes in rabbits era not
food indicate** of pregnancy status.
Body wslght changes may provids more
informatioa than • daily body weight
measored dormf treatment or during
gestation. Changes in weight during
treatment could occur that would not be
reflected in theoverafl weight change
throughout gestation, because of
compensatory weight gain that may
occur following treatment but before
•aerifies. For this reason, changes in
weight during treatment can be
examined as another indicator of
maternal toxicaty.
Changes in maternal body weight
corrected for gravid uterine weight at
sacrifice may indicate whether the effect
Is primarily maternal or fetaL For
example, there may be a significant
reduction in weight gain throughout
gestation and in gravid uterine weight
but no change in corrected maternal
weight gain which would indicate
primarily an intrauterine effect
Conversely, a change in corrected
weight gain and no change in gravid
uterine weight suggests primarily
maternal toxicity and little or no
intrauterine effect An alternate estimate
of maternal weight change during
gestation can be obtained by subtracting
the sum of .the weights of the fetuses.
However, this weight does hot include
the uterine tissue, placenta! tissue, or
the amniotic fluid.
Changes in other end potato should
also ba determined. For example.
changes in relative and abiralute organ
weights may be signs of miiternal effect
when an agent is suspected of causing
specific organ toxicity. Food and water
consumption data are usefoi especially
if the:agent is Administered in the diet or
drinking water. The amount ingested
(total and relative to body weight) and
the dose of the agent (relative to body
weight) can then be calculated, and
changes in food and water consumption
with treatment can be evaluated along •
w(th changes in body weight and body
weight gain. Consumatory data are also
usaful when an agent is suijpected of
affecting appetite, water intake, .or
•excretory.function. Clinical signs of
toxicity may also be used us indicators
of maternal toxicity. Daily body weight
i;h«ngg-» ij^ipng tr»mtTn>n» iilnng with
clinical observations may ?»e useful in
dsscribing ihs profile of miiternal
toxicity. ~
2. End Points of Developmimtal Toxicity
Bacmuss the maternal animal and not
the conccptusie the individual treated
during gestation, statistical analysis of
the data should conaider both the
individual fotui and the litter. Table 2
indicajtes the way in whick fetal and
litter end points can be'expressed.
TaMsS-EDdPohrtsofDeTriupmaaUl
AUUttut
No. implantstkm sites'/dam
No. coipora Intern (CLJ/dam^
Percsnt PreimplaaUtion loe»
No. and percent live -fetuses/Utter
-No. and Descent roaorptions/Iitter
No. and percent litters with resorptloni
No. mnd percent kte fetal desjhs/litter
No. and percent nonlive (late fctaJ death* +
re«orption>) implants/litter
No. and percent'litters with ntinlife implants
No. and percent affected (noniive +
malformed) implanU/litter
No. and percent with effected implants
No. and percent litters -with .total resorptiont
Litters .with 'live fetuMat
No. and percent -Utters with live fetuses
No. and percent Jive.fetuces/Utter
No. males/Utter
No. females/Utter
NaraMo/Utter
Mean (x) fetal body waight/Uttar
MMQ (x)male body weight/Utter
Mean (x) female body weight/litter
No. and percimt axternally malformed '•
:f«tuses/Btter
No. and paieaat vigcerali? malformed
'.fittnsM/litter
No.andp«rcaattk«J«laJ!yra«lfonned
lattuos/littar
No.aBdparc»aijaalJbraiadfetu9«s/lUter
No. and parcsnt litters with malfossaed
•fetuses . ' .
No. sad parcect malformad males/litter
No. and parcent malformad fescales/litto
No. and pwcent fetUM« with variatioiw/llttcr
No. and percsnt littara'havtag fahiMi with
variations
, Type* and incidence of individual
-.inauoRnaaons
'TypasaHdimddenea of individual yariatioat
Individual fstutes and their maifonnationi
and variationj (groupaii according to liHcr
anddoaa)
• Only when traataient begins prior to
nnplantation. May b« difficult Ui mice.
When treatment begins prior to
; implantation, an increaas in
preimplatation loss could indicate an
adverse affect either OR the developing
blastocyst or oathe process of
implantation itself. Further studies
would ba necessary to determine the
cause and extant of this type of effect.
The number of live fetuses per litter,
based on all litters, includes any litters
that have no live implants. On the other
hand, total nonlive implants
(postimplantation lose), is a combination
of me end points, reiprptions, and late
fetal deaths. An increased incidence per
litter for any of the end pointe indicating
postimplantation loss would be
considered a significant toxic effect to
'the conceptus. The number of litters
showing an increased incidence for
these end points is less useful than
'incidence per litter, because a litter is
counted whether it has .one or all
resorbed. dead.or nonliva implants.
A statisticaUy significant increase in
postimpiantation loss following
exposure to an agent is a severs form of
developmental toxjdty, but there is ,
considerable interlitter variability in the
incidence of postimplantation lossUT). If
a statistically significant increase is
: found after exposure to an .agent, the
data may be compared not only with
concurrent controls, but also with recent
historical control data. If a given study
control group exhibits an unusually high
,tjr;low incidence of postimplantation
loss compared to historical controls.
then scientific judgment would have to
be used to determine the'adequacy of
the studies for risk assessment purposes.
The end point for affected implants
(i.e.. the combination of nonliva and
-------
/ ¥©L 4a Ma. m / Friday, November 23. M84 /
... J..^^».,. ^..,.HjS>r,.^«.—^,»^y»:^^«mM^^'».«^^
• laddaestef fetdividuei typss e£ at Jerasts%-©k-(ag^ giaslsaas,-'!s
. .„-„. , ssalferasatians and vsriatioBS gives an soiventej.-thees d®vskipisseataJ effests-
sffid sasstass isadleatiera of thetypasofds^alepfBeatal shoaM ra@ bs ifassed,
dsvtettess fsedsaeed by a paitisuiar ' Approssfasss for ssEkisi ageats for
;gm a^afcA!i»tegi!ftBd.hfidja!i tfeefe ;«!«sti"*'* s
eawi gfvei sa todteatioa «f t8» pattern of
'
ft® fatis? snsswisss, &®@ is a grsate?
. msisnar, these should alsw fe gvainsted
as a
toxicitf . Tfes feteragaaey agsraife fefsi pssa tfes praatest thraat aisd'
„ doss-ralatsd- insg^ss in spoot^iseusiy
toceumng defects- as® asrsiwasst as
. .-*•.. . ..
wids-rsaai&fHied fetuses a?e!HEisg-
leltabta-indicatowofdevBtopawntai
inducible by sxogeooiiB agrals. an not
limited ;to dsatfe, steietisai
absujnaalitias, and altered growtk
,
Jo^idty thsa fe miKsfagr of Itttera wife Riathw. ithmlteaademosmtratediaa
do oat
dwfag attics? ctevafeamaoiad periods
iate htatssrseai1
te Sstsrpretstioa
eapssB% «^
factors that sheuld ba eersaf^sr^d to tUs- considering ail- zBaigmail and
evaJlua tiasa. of fetal' weight efeaagsSo Far dev-eiapHssErfaJ eod: psists ia orde?-to-
- - - ' , fetal
The vsris^f of gwstcssas assd end paints
that may ba evah5atsd"»s,t«Kj estensive
; (251. At gseseatno
W@k^fiaL 89 tasuuasay aaw^^^isssriy uvarmzrawswi 4*4»«i*^a-'«*«M*affifliii*ftww*»M^ «*»«*-.—«- ~~ «—— j
ws&Btocdze,aisdth8?^se?8nd'ofth* evalMa^osa-sif matesaBai toxhaty asdtte stinrfard te8tog.procedtoaft are
doBe^acaaiwairoiBaybecsafeaadsd doe®ieiz®l8-aiwMc&itcssffis thesstos nmtmeIymed,ais*tnMlia8lB«Jto
bw-aassiteSittesas^fe^sased'fetai- evaluBtiott-o£de««ie|HB8ataiti»uBity apparaat diss?epsamsa'tz8 the outooine
wei^t AddltiaassM^ tfe® av®sag® body and the-leweas-at ^kicfe Uasse- end poimte of csrtefc stssdies. Sess® attempte te
weigfetirftasls-^sisssta.^BsiSS'diaa. occu&tafsua^ an afea£ that produces gtandardtes-isarfevakatBpres^OTKri
that of female fei^as ia ta® m@sa changes is.as^ of the-torn E»ajo2 classes' are bsteg mads^. faa. fistenamatoa.
el dewalepmeatal tesssiSp ^ • d®s» dsmfc- of fustetSmMsl «5srap8toss-o«eH- Sswolvas
is mlmm&lly toais or not tosras tor taa higMy s^ada-llsecf —*-'-— —••*
sfeai^aJI . matam'ai animai is eonsidemi to have.
maifossaatiasss^Ilieal^ t
!ittss«8,c
;-3»asaiiJSiiifea-f5sJssted ffl^sHiall^' tsKcia doses- b$aBjente-te
^^^adsktfeiamamsgipsssEs ias5rc?iaaif- Qaturacfa
forKra
-------
4S32S
IH-42 ,
/ Vol. 4& No. 227 / Friday, November 23. 1964 / Notices
of Its biological significance and dote-
Tb« means for appropriate
intarpntation of data from functional
teratology sindfos is not always dear *
doe to the lack of knowkdga about the
toxicologfcai sigoifieaaea of spudfic
fancttoriil alterations. However, several
jtnaral coocepts hava arisen from tha
nowafca to data which may ba useful in
dtuipsinf stadia and evaluating data,
2. Several aspects rlitody design an
similar to than ns«d m standard
dewlopnmatal toxkirjr atodiia (e-g, a
approach with tha •
dot* producing minimal
maternal or fatal toxictiy, number of
litters ltrg» eocogh fee ade^tzato
statistical pow«p, nusdosizmtioxx of
animsJa to dot* group*. Utter generally
coesldend th» statistical unit etc.).
2. Replication of a study strengthens
th* confidence of data interpretation.
3. Ufa of a pharmacological challenge
may aid in evaluating function and
"unmasking'* effects not otherwise
detectable, particularly in the case of
organ systems that an endowed with a
reasonable degree of functional reserve .
capacity;
4. Choice of functional tests with a
moderate degfw of background
variability may be man useful in
deteetict effects of af«tt exposure than
testa based, on functional systems with
low variability that may be impossible '
to disrupt without being life-threatening.
Butcher et aL(27) have discussed this
with relation to behavioral end points.
S. A battery of functional tests is often
neceawuy to evaluate fully the
functional compateota of any given
system; thaw tests may need to be
conducted at several ages to account for
matufatioiial changes.
B. Critical periods for th* disruption of
functional competenc* may include both
th* prenatal period to tha time of
puberty, and the effect is likely to vary
depending on the time of exposure.
Although interpretation of functional
data may be difficult at present there
are at least two days in which the data
from these studies may be useful for risk
auwtmcnt purposes. First these
studies can be used to indicate whether
or not an agent has the potential to
cause functional alterations, and
whether these effects occur at doses
lower than those that produce other
forms of toxicity. Second, if the agent in
question is already in the environment
tha functional-data may be used for
focusing on organ systems to evaluate in
exposed h«""tn populations.
C SIwft'Tazsn Tsatmg in Deveiopnwnt
Toxitaty
The need for developmental toxicity
Samoa has arisen from the large
nomber of agents in or entering tha
environment and the increaned interest
in reducing 'tha number of animals used
in and the expense of testing. Currently.
two approaches are being considered for
their applicability in the overall testing
process: an in vivo mammalian screen
and a variety oSla vitro systems.
Neither approach is seen xt ithis time as
nplacmg current in vivo developmental
toxicity testing. Rather, they era being
considered for their usefulness in
assigning priorities for furthnr. more
extansrva testing.
l./a Vivo Mammalian Teratology
Screen
An in vivo approach developed by
Chamoff and KavIock(2S) uses the
pregnant mousa and it-designed to
reduce the resources required for
pracliminaryindication of
developmental toxicity.This approach is
based on the hypothesis that a prenatal
insult which results in-altered
development will be maaifeiited
postaatally as reduced viability and/or
impaired growth. In general the test
substance is adminiatered over the
period of major organegeneaia at a
single dosa level that will elidt some
degroa of maternal toxicity. After birth.
the pups era counted and weighed on
days 1 and 3. End points that are
considered in the evaluation .Include:
general maternal toxicity (including
survival and weight gain), litter size.
viability and weight of the offspring, and
gross malformations. Basic priority
categories for further testing have also
been suggested: (1) Agents that induce
perinatal death should receive highest
priority. (2) agents inducing perinatal
weight changes should be ranked lower
in priority, and (3) agents inducing no
effect should receive tha lowest
priority(29). The major goal of this test is
to predict the potential for
developmental toxicity of an agent in
the species utilized. It does mot increase
the ability to extrapolate risk to other
species, including'humans. Additional
studies to evaluate the validity of this
approach as a screen for developmental
toxicity are currently being carried out,
and a system for giving a numerical
ranking to the .results has been
suggested to prioritize agents for further
testingfaa 30).
2. In Vitro Teratology Screens
Test systems that fall under the
general heading of Hzn w/ro" include any
system that employs a test subject other
than the mtcst pregnant mammal These
systems have long bean used to assess
events associated with normal and
abnormal daveiopment but only
recently have they baea considered for
-their potential *s screens in testing (31,
32.32). Many of tfeate sysiems are now
being evaluated for^m®ir ability to
•predict m« developmental toxicity of
various cganta. This validation process
requires certaim considerations In study
design, iEclading defined end'points for
.toxicity and an understanding of the
system's ability to handle various test
agents(3£ 3*). A list of agents foip use in
these validatiottstudies has been
developed(J5}.
3.AppIieatioa
When ths validity of a screening
system is establiah9d.it may be used to
set priorities for further, more
" comprehensive in viva testing. In many
cases, a'betiery bftwo or more
screening systems may be needed,
employing tests with end points that
coUectiveiy represent'several
embryologic processes. In addition,
many of these systems can be applied in
an attempt to answer specific questions
of a dose-response, target-organ, or
mechanistic nature. Jh'vitro approaches
may aid in establiahing the effective
dose maireackea the target tissue.
Either thezh n'ro or in vitro short-term
approaches may be useful in addressing
stroetmre^ctivity relationships and the
synergiatic-antagonistis potential of
chemical interactions. Thus, pertinent
information can be derived from these •
approaches and may be useful in the .
assessment of potential risk.
D. Pharmasakmetics
Extrapoiatkm cf data between species
can be aided considerably by the
availebilityofdataonthe •
pharmacoirineHca of a particular agent
in the specie* tested and. if possible, in
humans. b£onsmtion on half-lives,
placenta! metabolism and transfer, and
concentrations of the parent compound
and metabolite* in tha maternal animal
and conceptus may be useful in
predicting risk for developmental
toxicity. Such data may also, be helpful
in. defining the dosa-response curve,
developing a more accurate comparison
of species sensitivity including that of
humans (38.37J, .determining dosimetry
at target sites, and comparing
pharmacokinstic profiles for .various
dosing regimefu or routes of exposure.
Pharmacokiaetic studies in
developmental toxicology are most
useful once » developmental toxic effect
has been produced in a give species
with a -parttcmlar agent Pharmacokinetic
-------
xxx-43
Refists? / Yel- 40. Mo. 227 / Friday, November 23, / Notices
data for risk assessment in
developmental toxicology ideally should
be derived horn pregnant females at the
stags when developmental insults occur.
QfSsn ths only data available are from
males, nonpregnant females, or from
nt feisalss at a tim@ ui&ralated to
the fetal period rtan malfomaticas
were induced eusij ia ofganogeneete).
Tha eorralattai of phasmacoMsjeas and
useful in determining the contribution of
specific pharataeo!ds@tts parameters to
Because of the ethical considerations
Mvoived. littl® human testing has bean
or ia likely to be done. Therefore, does-
effect developmental toxidty data from
humans are generally not available.
Human epidemiologic studies may
provide the best information for
assessing human risk and would reduce
the problems in spedes-to-spedes
extrapolation. However, interpretation
of epidemiology data must account for
smuounding factors, suds as maternal
•ise, parity, muttipla esspc
aasaiaiag accnmt
of
exposure lavels ia tine eovtaameiai,
points, etc. When human data are
available, they can ba used with othsr
supporting animal data to assess human'
risk.
F. Comparisons of Molecular Structure
Comparisons of the chamical or
ar~ nMt *•!•!• ««Q**««% wa«M
those of known dstasZo^mantal toxicants
may provide soms indication of a
potential for developmental toxidty.
Such infbgmatioa may ba useful in
priority-setting of Agents for testing or
for further evaluation when only
minimal data are available.
G. Weight-of-Evidence Determination
Information available from studies
discussed previously, whether indicative
of potential concern or not, must be
evaluated and factored into the
assessment The types of data may vary
from chemical to chemical and certain
types of data may ba more relevant than
otjier types of data in performing
developmental toxidty assessments.
Therefore, all data pertinent to
developmental toxidty should be •
examined in the determination of a
chemical's potential to cause
deveiopmsniai toxidty in humans.
Whatever evidence may exist from
humans must also ba factored into the
assessment.
IV. Qsaaotitaiiva Assessment
Risk assessment involves the
description of the natura and often the
magnitude of potential human risk,
including a description of any attendant
uncertainty. In the final phase of the risk
assessment, ma otatpute of the
qualitative evaluation, the dosa-
rscponse, and the exposure data are
combined to give qualitative and/or
quantitative estimates of the
developmental toxidty risk. As part of
me risif assessment, a summary of the
ateengtha and weaknesses of the hazard
identification, dose-response
assessment, exposure assessment, and
Major assumptions, sdentific judgments,
and, to the extent possible, estimates of
• the uncertainties in the assessment are
also presented.
A Dose-Responss Assessment
Because human dose-effect data
usually are not available, other methods
have bests used in developmental
toxicology for estimating exposure
Isvels that are unlikely to produce
sdvarsa effects ia Iranians. Tha does*
»apoa®8 assessment is usually baeed
' apoa tSss araluatton of taata performed
fa lataatory animals. Two approaches
frequently employed involve ths use of
safety factors and margins of safety,
which fa some respects are conceptually
similar. However, they are computed
differently and are often used in
different regulatory situations. The
choice of approach is dependant upon
many factors, including the statute
involved, t&a situation being addressed.
the data bass used, and ths needs of the
dsddon-maksr.
The safety factor approach is intended
to derive a calculated exposure level
that is unlikely to cause'any
developmental toxic responses in
humans. Ths size of the safety factor
will vary from agent to agent and will
require the exercise of scientific
judgment(3,39), taking into account
interspedes differences, ths nature and
extent of human exposure, the slope of
the dose-response curve, and the
severity of the developmental effects
observed at exposure levels below
maternal toxidty in the test spedea. The
safety factor selected is then divided
into the NOEL obtained from the most
spnrepriafaj and/or sensitive
mammalian species examined to obtain
an aecsptable exposure level Currently,
there is no one laboratory animal
species that can be considered most
appropriate for predicting risk to
httmans($}. Each agent she-aid be
The margin of safety approach dsrives
& ratio of ths NOEL from the most
sangifes spsdsss to the estimated
gGuress(4Q{. Use adequacy of ths margin
of safety ia then considered, bassed upoo
th© weight el svidsncs, including quality
of data, Rtsmbes of species affected,
doss-respons® relationships, aad other
As discussed earlier, ths prefemd
study design for a developmental
taicity study includes a lainimum of
tare® doseK a high dose that produces.
jainieaa! maternal toxidty, at least cue
intermediate doss, and a low dos@ that
demonstrates a NOEL Nevertheless,
there may be droimstancss in that there
is a nesd to perform a risk assessment
based on the results of a. study in which
& NOEL could not be identified, but
rather, in which this lowest doas
administered caused some nwginaHy
significant affeci(s). This lowest dose
could be identified as the lowest
observed effect level (LOEL). In
circuisstaaces where a LOEL can be
identified, it may bs appropriate to
apply an additional safety facto?. The
magnitude of this additional fsetor is
dependent upon scsumtific judgment IK
ba needed to afreragthes die confidence
in this additional safety factor.
The results of the dose-response
assessment are combined witSj an •
estimate of iusmaa exposure in order to
obtain a quantitative estimate of risk
The proposed Guidelines for Exposure
assd will not be discussed in,
any detail her®. &?. general fee exposure
exposure. This infomatta is developed
frcni monitorial! data aad from -
estimates based on modeling of
environmental exposures. Unique
considerations relevant to
developmental toxidty are duration and
period of exposure as related to stage of
gestation (ie., critical periods), and the
fact that a aitigis ssspoem-a may be
eufSeiest to produce adverse
developmental affects (i.e., chronic
exposure is not necessary for
developmental toxicity to be
manifested). s
There are jsuiaerouB uncertainties
asscciaied with tha Joxicological and
exposwe compeaeiata of risk assessment
that in tfea past have often sot been '
-------
IXX-44
41331
SfeJsss! Kagnte / V^L.48.
pnwcstwi. T^w pMttdt
qoalitativ*) cr qontitsthn risk
'
cancarnfrtg tit* qpditjf.of tfa« data*
'
of Kid octets ?»»« fiv.tiM.QthjSI' GQfi
.
]| racaooc oaly, cJiaagd iafetal
weight ua oflea daestfabla at doasa
btlow thos« producing after alpis of
At pTCSHlt. tima ij DO
At pTCS
model tha
[ that is generally Quad fox
estimating developmental toxicity
response* below tha applied doB* range/
Thl» is due primarily to tha lack of
'tmdatstanding of tha biological
mechanisms underlying developmental
toxicity, intra/interspadss differences in
tho types of developmental-events, the-
influence of maternal effects on the
doto-rtsponsa curva. and whether or not
• threshold exists below which no effect
will be produced by an agent The
assumption of a threshold is based
largely oa the biological rationale that
th* embryo is known to hava some
capacity for nrpair of tha damags or
in«\ilt(*?), and. that-most developmental
davialions are probably multifactorial m
E«terc{<3)>.Havif:sv8r, the esdiBtenc* of <•'•-
so effect ifffc! caamoi be proi^aa
statistically.
Dfsouaioms.of risk extnpolation-
a'ire noted thai farther work
&x ccEJrolIiEgrisk.that coasliinas tha
VSM ft ^s^^timmiirjil mndatarfag lovto •
dc-3 ostisEatioE cf.risk.with ffia:
fiiGtoibasffldoaa.
apgEosch is similar to. appraiichea.
propos-d'for card
t&issMolii; and'may pnmda «-moi»
quaatilathrc appteacE'to COB trolling
risSc. For. th* present, tha Ageacy will'
CJKzaEua to uai. safstjf
apptopriati modsle will ba sought and
applied if coot ides^d acceptsble.
£oss8
pPocediiTss that the U.S. Environmental-
Erotfictidn Agpney will fbllnw in
evaluating the potential for tigents to
cause dsvalbpxngntal toxidtf|r. Thesa
Guidelines wiftbcr reviewed and
updated aa.edvancea are made in tha-
fiU^.aioffisit la ovidantthatwuE ability.
to sva&its asd paedict humiin
'
Fnrtlte? cicdiea tSiat.delinaatB the
toxicity,
and'pathogenesiikpravidecnntparaiiva
phamacokicetiE data, and elucidaie the
functioaal modalities that may. be
alterad by expooura to toxic, agents will
aid in tha interpratation of data and
intesap^des extrapolation. These types
ofchidiesa,.alG3gwith.fiiztheiJ«valuatioh
aHmiahip hatwmm
and fetal toxicity and the concept of a
timshold in developmental Coxicity. win
provide for die development of
ispsovcd mathamaticaimoelels to more ;
nndsely assess risk. • 1
{31 UA BtnrfroaiBBntml Protection Agency.
1862. Health eSacU last guidelines. Chaplw
IL Specific «gan/tis«u« toxidty-
tuMtoganicity. Office of Toxic Substanca*.
Availablsfrom:NTIS.Springfie1d..VA.PB8^
232984.
(2) U.S. Emrironmontal PrbteaUoir Agency.
1930. Assosfment of risks to human ~
repmduetion and lo development of the
humtiB ooncephu from nxposuni to
envirojsascatai nibatances, pp. £16-116.
Available ftoss: NTiS. Springfield. VA. DEaz-
007997.* "
( 5) U43. Environmeatai Protection Agency.
1682. Pesticide* regislration: prtipoad data
rsqnlrsiaiiaSs. Federal RegiaSer 47-^31 92-
53203.
(4) Hcrtig. AIT. 1B67. -Hia ovarail probltm
ta man. In: if. Beoiicchke. ad. Comparnttvn
aspsrets o€
NYJ
iwa faiiiinB. J*I«w York.
Meiltenuatiaa«,iB a pcpulaiiaa obMrved-for
five ywrs afterbirth^ las GJ.W.
. ed§^ Qba
duingiti Ji
, Med. : Asses,
drags jiaiaasifeJ.Gi SWlssa and F.C. Prasor.
•di. Hiffidbcok cfteatology. Now Yotfc J*.Tf:
Stsnom Press, pjjfcOB-SSS.
t»«tog«siic asestSi Third EditioB. Baltimore.
MD: Johns Hopkins Uahraswty&esa.,
(^ Scbardain. Ji. 1983. TotstogsniB risk
aaaessEHOfaJo: H. Kfiiter; ed. itaae* snd.
swtewaJa tesalofogy, VoLl. Mew YorteOflYi
ssBnis*, pa.- 181-214.
J Sbipanl TJi.l9S4,.TcratogsKK an.
(IJ) Brnwo, NJU asi'S. FaBKX 19«3. Tho
Tmlosofsniznalteratogeffljiiityieaticsfcr
predicting Jnanzss risk. CUffl. OBsSet; Gyneco!.
28M67i«Tr
(12) Kinmd; CA- JJ'; HO!»OBI; GJ. Hogw.
Report fiw 'S^ptgUatat KtK.emS. NCTRi
, ,
(19) CosanriK»«.on.the.!inaSihitionaJ Maene .
for ti» Asssssaaentsof itisfaL-ta.-2ub1lc Health.
1983. Ri«K ««»eieaMSt.to tKaJPederal
govaram«B
gciaat Sdaansn. Nt
ReMareh GbondtWaaMngton. DC National
Acsdausy Press, pp. W-83>
(H] Food «nd Brog Adijnisiittration. 1S68.
Guidelinas for reproduction and teratology of
drug*. Buraau of Drags.
(73) Pood and'Drug Adintafatration. 1970.
Advisory CommitteaoiLPjpotQcols for Safety
Evaluations. Fiscal oa .Reproduction Report .;
on Reproduoaoa Studies in tKa Safety
Evaluation of Food'AddiUvaii and Pesticide
Retidnsa. TojdcoL AppL PhnnnacoL 16264-
298.
(Jfl) Sympc»isim oa-«ffeotii of radiation and .
otbor.dai*terfaiis;eg«ita «n>erabrymiic>
development; 196fc j. CalL.Coaap. Phyaio!. 43
(tuppkl).
(17) Woo. D.C^and:RAt Hoar. 1879;-:
Reprodustive performance and spontaneous.
malformationt ia control Charles Rivar rats.
A joint-studs for MARTA. Teratology 19.-S4A.
(IS) Interagency Regulatory Liaiaon Group.
1961: Report of the Developmental Toxicity
End Points Workgroup. Workshop on
Reproductive Toxicity RiskvAsEcsimem.' '
Roekville; MD,Septcsajbcr 21-23. ,
(79) Johaaca. EJd. 1881. Screening for:
teratogenic hazards-nature .of Ihe problem;
Annu. Rav. PharmacoLToxicCTk 21:417-129.
(2O\ Johazoa. £M» and B^.G. CabaL 1833.
An artificial embryo for detection of •
abnormal developmental biology.; Fund; Appl.
ToxicoL 3-J!43~2€a
(21) Fabro. •&.' G. SchulL and N^=L Brown.
1082. The relativa tentogenic index and.
teratonenin potency: propowsd uompanenti of
-------
m-45
/V©L_49, N0..227/ Friday. November 23, 1884 / Notlees .
4S331
dswslopiBssSsl toxieity risk soessamsnt.
Tasstogsnasis Careinog. Mutagea. 2m-7&
(28J Johnson. &M. 1884. A priorii&atfem
and biological dccisiea tree for
As. Call T«Kskai 3.141-1*?.
(S3] Kedier. RM. tem Bsfeavteal
teratology. Its J.G, WUfoa end F.C Prase?.
eda, Handbook ef teratology. Vol. 4. New
York. NY: Hemssa Rress. pp. 397-42a
end CA, KtasoeL 1S?8.
DawJopsassst SEM stasMardlaatiaiB of
(2S) Ksviock. R.J.. aad CT. GrabowafcL eds.
fssBCJloeaJ tesatalegy. Prog. Ola. Biol Res,
VoL 140. N«w? York. NY: Alan 8. Uss. fafc
(5S) KfauBsl C&, J. Easj&e-Saai, f. Adams.
L.W. Reiter. T.J. Sobotkc. aad HA. TUeon.
1SS2. Dasigss eenjjdsratiosifi ia tha evaluatiQa
of stnmfedted ms&ads in a behavioral
tssatotegy etisdy. Taratclogy 2S^4A.
(2?J ditcher. ItE. V. W«jolea. end C.V.
teratology teasing: test verisbilify and
. TejaJogeissMJs Caisaaog, MuUegao.
(28) Ossmoa; R, and R.J. Kavlock. 18S2,
An in vivo t^atoid^ Mseea uijlizing
prsgaffiat mice. J. TosdesL Environ. Health
(£9) Ssfflwa. J J4. 1SS& ValidatJoa of aa ia
of erabsyo/
Ssaith. 1984. Results of tssKsg flftssn glywl pregnant rats and rtaus monkeys. TQticoi.
toaddty assay. Eravte^. Haslta. Perspact, ia C^l KtaaseL CA» and J.F. Young. 18*3.
• sygtetBK thsir poteEtisl i5«s in fswsiogsjsia:^
ssfssening. In: J.G. WtSsoa w& F.C. ?rasc».
edn. Handbook of teratojssgj?, Vtii 4. New
Yarfc. NY: H^sum I^ess. pp. 135^183.
(32! Kfessal GJ» 1C Eiaith. DJ^i KasEfcar.
Caralnog. Matagea. &221-229.
(53J Browa. N-A, aad &B. Fabro. S^a'The
/is vitro apprasdi to icroSogaRicily tasting. IK
K. SnsO. ed Dsvclsspjaenta] Jsssdeolsgy.
leKidca fisglaad: &»QH-Ks!as, pp. 31-67.
(5«) Kimssd. GX. 1984. & wfcw tests ia
SCTBosisisg teratogsns: scarndCTaHoEa to aid
the vstidattoa'pseeesa. Is: M. Heriia. ed
Pnmmtiea of pisyakal aad mental eetcgessital
defects. Pan A. New Yorit. NY: Alaa R. Lias.
,!E&, Izs jgsss,
, (SSJ Smith. M^GX-Kianas!. DAI
Kochhar. TJi Shepajd, 3J>. Spisiberg, aad
J.G. Witsen. 1883. A isJsstioa of candidate
eofflpciaada for in vitro tepaJoganesis teat
validation. Teratoganesis Carcinog. Miitagsn.
'
(38) Wifeoa. J.G> W.J. Scott. E.f. Ritter. sad
R. Fradkia, 1S7S. Coraparative distribution
pragaaat sate asd thssm swnkeys.
(»J Wtass. J.G, U. Mltar. WJ. Scott, aad
E, FradMB. JS??. Comparative dlaSHfcisKoa
ToxicoL 3^S®-355.
(£S>) Hs-gsa. MB, aa^ B.C. H^sL 1882.
S:st!apcisa&-n SB mssis. IK A.W. Hayas. ed.
.ftlaeptes ^sd neilteds at toxicology. New
Yosfe, NY: Eavss PBS»S, pp. 711-731.
1.4S) Oitlik. UJ, Q.Q. Bui. G.J. Buria, aad
S.C, Bepsea. 1SSS4. Stsndard evaiuatioQ
prseedurog for te^tolog^ studiea PraftJ.
TessdKjiogy Braadt, Hazard Evaluation
S'lviaiea Og-ic-o of Pesticide Pwgrasns, U^.
Esirojimsatei i?rof.5!£tioa Agency.
(41} Keiscsn, Cf, and ]$. Holson. 1978.
Ssscblsssjs aad adwasssassents.^. Saviraa.
PstteL To«isoi aaw-i^.
(48J Witeoa. |.G. i973. EavironisssaS and
birth defeat®. New Yodc, NY: Acadesnc Fsess.
pp. SS-32.
{43} Fyaaar. F.C 1S77. RalaJian of aaimal
afeuJies to th« prabtem is. man. In: J.G. Wilaon
aad F.C F^sssf. ads. Handbook of temtetogy.
VoL 1. New York. NY: Plaaiira Freaa, pp. 7S-
§8.
(<«•) EEvirooaaenial Health Criteria 30.1834.
Principles for evaluatuig health risks to
progeny associated with exposure to
chemicals during pregnancy, pp. 111-114.
World Health Organization. Geneva.
Switesriand.
(4S} Gajrto. O.W. 3S83. The us® of safety
-------
------- |