34014
Federal Register / Vol. 51. No. 185 / Wednesday. September 24. 1988 / Notices
ENVIRONMENTAL PROTECTION
AGENCY
[FRL-2984-2J
Guidelines for the Heatth Risk
Assessment of Chemical Mixtures
AGENCY: U.S. Environmental Protection
Agency (EPA).
ACTION: I-'inal Guidelines for the Health
Risk Assossment of Chemical Mixtures.
SUMMARY: The U.S. Environmental
Protection Agency is today Issuing five
guidelines for assessing the health risks
of environmental pollutants. These are:
Guidelines for Carcinogen Risk
Assessment
Guidelines for Estimating Exposures
Guidelines for Mutagenicity Risk
Assessment
Guidelines for the Health Assessment of
Suspect Developmental Toxicants
Guidelines for the Health Risk
Assessment of Chemical Mixtures
This notice contains the Guidelines
for the Health Risk Assessment of
Chemical Mixtures; the other guidelines
appear elsewhei-e in today's Federal
Register.
The Guidelines for the Health Risk
Assessment of Chemical Mixtures
(hereafter "Guidelines") are intended to
guide Agency analysis of information
relating to health effects data on
chemical mixtures in line with the
policies and procedures established In
_illS-?.tatujes,adml.nisteredj)y th_e..EPA»
These Guidelines wera developed as
part of an interoffice guidelines
development program under the
auspices of the Office of Health and
Environmental Assessment (OHEA) in
'.he Agency's Office of Research and
Development. They reflect Agency
.consideration of public and Science
Advisory Board (SAB) comments on the
Proposed Guidelines for the Health Risk
Assessment of Chemical Mixtures
published January 9,1985 (50 FR 1170).
This publication completes the first
round of risk assessment guidelines
development. These Guidelines will be
revised, and new guidelines will be
developed, as appropriate.
EFFECTIVE DATE: The Guidelines will be
effective September 24.1988.
FOR FURTHER INFORMATION CONTACT:
Dr. Richard Hertzberg, Methods
Evaluation and Development Staff,
Environmental Criteria and Assessment
Office, U.S. Environmental Protection
Agency, 26 W. St. Clair Street,
Cincinnati, OH 45208, 513-569-7582.
SUPPLEMENTARY INFORMATION: In 1983,
the National Academy of Sciences
(NAS) published its book entitled Risk
Assessment in the Federal Government:
Managing the Process. In that book, the
NAS recommended that Federal •
regulatory agencies establish "foference
guidelines" to ensure consistency and
technical quality in risk assessments
and to ensure that the risk assessment
process was maintained as a scientific
effort separate from risk management. A
task force within EPA accepted that
recommendation and requested titat
Agency scientists begin to develop such
guidelines.
General
The guidelines published today ara
products of a two-year Agencywida
effort, which has included many
scientists from the larger scientific
community. These guidelines s«t forth
principles and procedures to guide EPA
scientists in the conduct of Agency rink
assessments, and to inform Agency
decision makers and the public about
these procedures. In particular, the
guidelines emphasize that risk
assessments will be conducted on a
case-by-case basis, giving full
consideration to all relevant scientific
Information. This case-by-case approach
means that Agency experts review the
scientific information on each agent and
use the most scientifically appropriate
interpretation to assess risk. The
guidelines also stress that this
information will be fully presented in
Agency risk assessment documents, and
that Agency scientists will identify the
strengths and weaknesses of each
assessment by describing' uncertainties,
assumptions, and limitations, ar well as
the scientific basis and rationale for
each assessment.
Finally, the guidelines are formulated
in part to bridge gaps in risk assessment
methodology and data. By identifying
these gaps and the importance of She
missing information to the risk
assessment process, EPA wishes to
encourage research and analysis that
will lead to new risk assessment
methods and data.
Guidelines for Health Risk Assessment
of Chemical Mixtures
Work on the Guidelines for the Health
Risk Assessment-of Chemical Mixtures
began in January 1984. Draft guidelines
were developed by Agency work group*
composed of expert scientists from
throughout the Agency. The drafts were
peer-reviewed by expert scientists in the
fields of toxicology, pharmacoldnetics.
and statistics from universities.
environmental groups, industry, labor,
and other governmental agencies. They
were then proposed for public comment
in the Federal Register (50 FR 1170}. On
November 9,1984. the Administrator
directed that Agency offices use the
proposed guidelines in performing risk
assessments until final guidelines
become available.
After the close of the public comment
period. Agency staff prepared
summaries of the comments, analyses of
the major Issues presented by the
commentors, and preliminary Agency
responses to those comments. These
analyses were presented to review
panels of the SAB on March 4 and April
22-23, 1985, and to the Executive
Committee of the SAB on April 25-26.
1965. The SAB meetings were - »
announced in the Federal Register as
follows: February 12. 1985 (50 FR 5811)
and April 4. 1985 (50 FR 13420 and
13421).
In a letter to the Administrator dated
June 19, 1985, the Executive Committee
generally concurred on all five of the
guidelines, but recommended certain
revisions, and requested that any
revised guidelines be submitted to the
appropriate SAB review panel chairman
for review and concurrence on behalf of
the Executive Committee. As described
in the responses to comments (see Part
B: Response to the Public and Science
Advisory Board Comments), each
guidelines document was revised, where
appropriate, consistent with the SAB
recommendations, and revised draft
guidelines were submitted to the panel
chairmen. Revised draft Guidelines for
the Health Risk Assessment of chemical
mixtures were concurred on in a letter
•letters are available at the Public
Information Reference Unit. EPA
Headquarters Library, a's" indicated
elsewhere In this notice.
Following this Preamble are two parts:
Part A contains the Guidelines and Part
B. the Response to the Public and
Science Advisory Board Comments (a
summary of the major public comments,
SAB comments, and Agency responses
to those comments).
The SAB requested that the Agency
develop a technical support document
for these Guidelines. The SAB identified
tha need for this type of document due
to th« limited knowledge on interactions
of chemicals in biological systems.
Because of this, the SAB commented
that progress in improving risk
assessment will be particularly
dependent upon progress in the science
of interactions.
Agency staff have begun preliminary
work on the technical support document
and expect it to be completed by early
1987. The Agency is continuing to study
the risk assessment issues raised in the
guidelines and will revise these
Guidelines in line with new information
as appropriate.
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Federal Register / Vol. 51. No. 185 / Wednesday, September 24. 1986 / Notices
34015
References, supporting documents,
and comments received on the proposed
guidelines, as well as copies of the final
guidelines, are available for inspection
and copying at the Public Information
Referenco Unit (202-382-5926). EPA
Headquarters Library, 401 M Street, SW.
Washington, DC. between the hours of
8:00 a.m.-and 4:30 p.m.
I certify that these Guidelines are not
major rules as defined by Executive
Order 12:291, because they are
nonbinding policy statements and have
no direct effect on the regulated
community. Therefore '.hey will have no
effect on costs or prices, and they will
have no other significant adverse effects
on the economy. These Guidelines were
reviewed by the Office of Management
and Budget under Executive Order
12291.
Dated: August 22, 190fl.
Le« M.Tl>omn«,
Administrator. '
Contents
Part A: Guidelines for tho Health Risk
Assessment of Chemical Mixtures
/. Introduction
II. Proposed Approach
A. Dntn Available on the Mixture of Con-
cern
B. Data Available on Similar Mixtures
C. Datu Available Only on Mixture Com-
ponents
1. Systemic Toxicants
2. Carcinogens
3. Interactions
4. Uncertainties
a. Health Effects .
b. Exposure Uncertainties
c. Uncertainties Regarding Composi-
tion of the Mixture
///. Assumptions and Limitations
A. Information on Interactions
B. Additivity Models
IV. Mathematical Models and the Measure-
ment of Joint Action
A. Dose Addition
C. Response Addition
C. Interactions
V. Hvfpn'nces
Part B: Response to Public and Science Advi-
sory Board Comments
/. Introduction
II. Recommended Procedures
A.. Definitions
B. Mixtures of Carcinogens and Systemic
Toxicants
///. Additivity Assumption
A. Complex Mixtures
B. Dose Additivity
C. Interpretation of the Hazard Index
D. Use of Interaction Data
IV. Uncertainties and the Sufficiency of the
Datu Vase
V Need for a Technical Support Document
Part A: Guidelines for the Health Risk
Assessment of Chemical Mixtures
/. Introduction
The primary purpose of this document
is to generate a consistent Agency
approach for evaluating data on the
chronic and subchronic effects of
chemical mixtures. It is a procedural
guide that emphasizes broad underlying
principles of the various science
disciplines (toxicology, pharmacology,
statistics) necessary for assessing health
risk from chemical mixture exposure.
Approaches to be used with respect to
the analysis and evaluation of the
various data are also discussed.
It is not the 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
agent{s). AH such action is addressed in
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
mixture of compounds that may induce
similar or dissimilar effects over
exposure periods ranging from short-
term to lifetime. For the purposes of
these Guidelines, mixtures will be
defined as any combination of two or
more chemical substances regardless of
source or of spatial or temporal
proximity. In some instances, the
-•mbctttres are-highry complex-correhrlmg -
of scores of compounds that are
generated simultaneously as by-
products from a single source or process
(e.g., coke oven emissions and diesel
exhaust). In other cases, complex
mixtures of related compounds are
produced as commercial products (e.g.,
PCBs, gasoline and pesticide
formulations) and eventually released to
the environment. Another class of
mixtures consists of compounds, often
unrelated chemically or commercially,
which are placed in the samo area for
disposal or storage, eventually come
into contact with e^ch other, and are
released as a mixture to the
environment. The qualily snd quantity
of pertinent information evailable for
risk assessment varies considerably for
different mixtures. Occasionally, the
chemical composition of a mixture is
well characterized, levels of exposure to
the population are known, and detailed
toxicologic data on the mixture are
available. Most frequently, not all
components of the mixiure are known,
exposure data are uncertain, and
toxicologic data on the known
components of the mixture are limited.
Nonetheless, the Agency may be
required to take action because of the
number of individuals at potential risk
or because of the known toxicologic
effects of these compounds that have
been identified in the mixture.
The prediction of how specific
mixtures of toxicants will interact must
be based on an understanding of the
mechanisms of such interactions. Most
reviews and texts that discuss toxicant
interactions attempt to discuss the '
biological or chemical bases of the
interactions (e.g., Kteaseen and Doull,
1990; Levine. 1973: Goldstein et al.. 1974;
NRC, 1980a; Veldslra. 1956; Withey,
1981). Although different authors use
somewhat different classification
schemes when 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,
metabolism, excretion, and activity at
the receptor site(s). Compounds may
interact chemically, yielding a new toxic
component or causing a change in the
biological availability of the existing
component. They may also interact by
causing different effects at different
receptor sites.
Because of the uncertainties inherent
in predicting the magnitude and nature
of toxicant interactions, the assessment
• of health risk from chemical mixtures —•
must include a thorough discussion of
all assumptions. No single approach Is
recommended in these Guidelines.
Instead, guidance is given for the use of
several approaches depending on the
nature and quality of the data.
Additional mathematical details are
presented in section IV.
In addition to these Guidelines, a
supplemental technical support
document is being developer! which will
contain a thorough review of all
available Information on the toxicity of
chemical mixtures and a discussion of
research needs.
//. Proposed Approach
No single approach can be
recommended to risk assessments for
multiple chemical exposures.
Nonetheless, general guidelines can be
recommended depending on the type of
mixture, the known toxic effects of its
components, the availability of toxicity
data on the mixture or similar mixtures,
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Federal Register / Vol. 51, No'.' 185 /Wednesday, September 24, 1988 / Notices
the known or anticipated interactions
amoiig components of the mixture, and
the quality of the exposure data. Given
the complexity of this issue and the
relative paucity of empirical data from
which sound generalizations can.be
constructed, emphasis must be placed
on flexibility, judgment, and a clear
articulation of the asrumptions and
limitations in any risk assessment that is
developed. The proposed approach Is
summarized in Table 1 and Figure 1 and
is detailed below. An alphanumeric
scheme for ranking the quality of the
data used in the risk assessment is given
In Table 2.
A. Data Available on the Mixture of
Concern
For predicting the effects of •
subchronic or chronic exposure to
mixtures, the preferred approach usually
will be to use subchronic or chronic
health effects d&ia oil the mixture of
concern and adopt procedures similar to
those used for single compounds, either
systemic toxicants or cavcinogens (see
U.S. EPA, 1986a-c). The risk assessor
must recognize, however, that dose-
response models used for single
compounds are often based on
biological mechanisms of the toxicity of
single compounds, and may not be as
well justified when applied to the
mixture as a whole. Such data are most
likely to be available on highly complex
mixtures, such as coke oven emissions
or diesf:! exhaust, which are generated
in large quantities and associated with
- orsttspected of causing adverse health •
effects. Attention should also be given
to the persistence of the mixture in the
environment as well as to the variability
of the mixture composition over time or
from different sources of emissions. If
the components of the mixture are
known to partition Into different
environmental compartments or to
degrade or transform at different rates
in the environment, then those factors
must also be taken into account, or the
confidence in and applicability of the
risk assessment is diminished.
T»bl« 1.—Risk Assessment Approach for
Chemical Mixture*
1. As»e»« the quality of the data on
Interactions, health effects, and exposure (see
Table 2). .
a. If adequate, proceed to Step 2.
b. If Inadequate, proceed to Step 14.
2. Health effects Information Is available
on the chemical mixture of concern.
a. If yes. proceed to Step 3.
b. If no, proceed to Step 4.
• 3. Conduct risk assessment on the mixture
of concern based on health effects data on
the mixture. Use the same procedures as
those for single compounds. Proceed to Step 7
(optional) and Step 12.
4. Health effects Information Is available
on a mixture that Is similar to the mixture of
concern.
a. If yes. proceed to Step 5.
b. If no, proceed to Step 7.
S. Assess the similarity of the mixture on
which health effects data are available to the
mixture of concern, with emphasis on any
differences In components or proportions of
components, as well as the effects that such
differences would have on biological activity.
a. If sufficiently similar, proceed to Step 6.
b. If hot sufficiently similar,.proceed to
Step 7.
6. Conduct risk assessment onjhe mixture
of concern based on health effects data on
the similar mixture. Use the same procedures
as those for single compounds. Proceed to
Step 7 (optional) and Step 12.
7. Compile health effects and exposure
information on the components of the
mixture.
8. Derive appropriate Indices of acceptable
exposure and/or risk on the Individual
components In the mixture. Proceed to Step 9.
9. Aosess data on Interactions of
components In the mlKtursr-
a. V sufficient quantitative data are
available on the interactions of two or more
components In the mixture, proceed to Step
10.
b. If sufficient quantitative data are not
available, use whatever Information is
available to qualitatively Indicate the nature
of potential Interactions. Proceed to Step 11. .
10. Use an appropriate Interaction moilol to
combine risk assessments on compounds for
which data are adequate, find use an
addltlvlty assumption Tor the remaining
compounds. Proceed to Slop 11 (optional) and.
Step 12.
11. Develop v risk assessment based on an
addltlvlty approach for all compounds In the
mixture. Proceed to Step 12. .
12. Compare risk assessments conducted In
Steps 5. 8. and 9. Identify and justify the
preferred assessment, and quantify
uucertalnty, if possible. Proceed to Step 13.
13. Develop an Integrated summary of the
qualitative and quantitative assessments
with special emphasis on uncertainties and
assumptions. Classify the overall quality of
the risk assessment, as Indicated in Table 2.
Stop.
14. No risk assessment can be conducted
because of Inadequate data on Interactions,
health effects, or exposure. Qualitatively
assess the nature of any potential hazard and
detail the types of additional data necessary
to support a risk assessment. Stop.
Note.—Several decisions usad here,
especially those concerning adequacy of data
amd similarity batween'lwo mixtures, are not
precisely characterized and will require
considerable judgment. See text
BILUNQ COOC «S«O-C6-M
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3
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rt o
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34018
Federal Register / Vol. 51, No: 185 / Wednesday, September 24. 1886 / Notices
Table 2.—Classification Schema for the
Quality of the Risk Assessment of the
Mixture*
Information on Interactions
I.'Assessment ts based on data on the
mixture of concern.
II. Assessment Is based on data on a
sufficiently similar mixture.
HI. Quantitative interactions of components
are well characterized.
IV. The assumption of addltlvlty Is justified
based on the'nature of the health effect? end
on the number of component compounds.
V. An assumption of addltlvlty cannot bo
justified, and no quantitative risk assessment
can be conducted.
Health Effects Information
A. Full health effects data ere available
and relatively minor extrapolation Is
required.
. B. Full health effects data are available but
extensive extrapolation ts required for route
or duration of exposure or for species
differences. These extrapolations are
supported by pharmacoklnelic
considerations, empirical observations, or
other relevant Information.
C. full health effects data are available.
but extensive extrapolation is required for
route or duration of exposure or for species
differences. These extrapolations are not
directly supported by the-Information
available.
D. Certain important health effects data are
lacking and extensive extrapolations are
required for route or duration of exposure or
for species differences.
E. A lack of health effects information on
the mixture and Us components In the
mfxlure'precludes a quantitative risk
assessment.
Exposure 'Information'
1. Monitoring information either alone or in
combination witK modeling information is
sufficient to accurately characterize human
exposure to the mixture or Its components.
2. Modeling information is sufficient to
reasonably chararisrize human exposure to
the mixUire or Its components.
3. Exposure estimates for some components
are lacking, uncertain, or variable.
Information on health effects or
environmental chemistry ruggest that this
limitation is not akely to substantially affect
the risk assessment.
4. Not all components in the mixture have
been Identified or levels of exposure are
highly uncertain or variable. Information on
health effects or environmental chemistry is
not sufficient to assess the effect of this
limitation on the risk assessment.
5. The available exposure information is
tastilficient for conducting a riak assessment.
'See text ford'«cus»ic-.i>f ic-ffic'c'-l similarity.
.••dequacy of data, an''. j>:>tKicMian for t^dilivity
Asftumplicma.
* See the Agcncj « .. •it?'y.:ni r f"f I .:'imating
r^'tr.tires (U.S. E"\." '>ij f'.»r on.rp -omplcte
fi-,r;r.-'7'.ior on perio . ..-C'.r - asjensmnnU
and . -limiting the quality T. .o»ure dels.
B. Data Available on Similar Mixtures
If the risk assessment is based on
data from a single mixture that is known
to be generated with varying
compositions depending on time or
different emission sources, then the
confidence in the applicability of the
data to a risk assessment also is
diminished. This can be offset to some
degree'if data are available on several
mixtures of the same components that
have different component ratios, which
encompass the temporal'or spatial
differences in composition of the
mixture of concern. If such data are
available, an attempt should be made to
determine if significant and systematic
differences exist among the chemical
mixtures. If significant differences are
noted, ranges of risk can be estimated
based on the toxicologic data of the
various mixtures. If no significant
differences are noted, then a single risk
assessment may be adequate, although
the range of ratios of the components in
the mixtures to which the risk
assessment applies should also be given.
If no data are available on the
mixtures of concern, but health effects
data are available on a similar mixture
(i.e., a mixture having the same
components but in slightly different
ratios, or having several common
components but lacking one or more
components, or having one or more
additional components), a decision must
be made whether the mixture on which
health effects data are availablais.or is
not "sufficiently similar" to the mixture
of concern to permit a risk assessment.
The determination of "sufficient
similarity" muut be made on a case-by-
case basis, considering not only the
uncertainties associated with using datn
on a dissimilar mixture but also the
uncertainties of using other approaches
such as additivity. In determining
reasonable similarity, consideration
should be given to any information on
the components that differ or are
contained in markedly different
proportions between the mixture on
which health effects data are available
and the mixture of concern. Particular
emphasis should be placed on any
toxicologic or pharmacokinetic data on
the components or the mixtures which
would be useful in assessing the
significance of any chemical difference
between the similar mixture and the
mixtures of concern.
Even if a risk assessment can be made
using data on the mixtures of concern or
a reasonably similar mixture, it may be
desirable to conduct a risk assessment
based on toxicity data on the
components in the mixture using the
procedure outlined in section H.B. In the
case of a mixture containing carcinogens
and toxicants, an approach based on the
mixture data alone may not be
sufficiently protective in all cases. For
example, this approach for a two-
component mixture of one carcinogen
and on* toxicant would use toxicity
data ou the mixture of the two
compounds. However, in a chronic study
of such a mixture, the presence of the
toxicant could mask the activity of !.'••"
carcinogen. That is to.say, at doses of
the mixture sufficient to induce a
carcinogenic effect,' the toxicant could
Induce mortality so that at the maximum
tolerated dose of the mixture, no
carcinogenic effect could be observed.
Since carclnogenlclty is considered by
the Agency to be a nonthreshold effect,
it may not be prudent to construe the
negative results of such a Moassay as
indicating the absence of risk at lower
doses. Consequently, the mixture
approach should be modified to allow
the risk assessor tc evaluate the
potential for masking, of c:ie effect by
another, on a case-by-case basis.
C. Data Available Only on Mixture
Components
If data are not available on an
identical or reasonably similar mixture,
the risk assessment may be based on
the toxic or carcinogenic properties of
the components in the mixture. When •
little or no quantitative information is
available on the potential Interaction
amo.ng-the.componentBi«_additiyejnodel8
(defined In the next section) are
recommended for systemic '.oxicantc.
Several studies have demonstrated that
dose additive models often predict
reasonably well the lox.ir.itie-: of
mixtures composed of a substantial
variety of both similar and dissimilar
compounds (Pozzani et al., 1959; Smyth
et al., 1969.1970; Murphy, 1980). The"
problem of multiple toxicant exposure
has.been addressed by the American
Conference of Governmental Industrial
Hygienists (ACG1H, 1983). the
Occupational Safety and Health
Administration (OSHA, 1983), the World
Health Organization (WHO. 1981), and
the National Research Council (NRC,
1980a,'b). Although the focus and
purpose of each group was somewhat
different, all groups that recommended
an approach elected to adopt some type
of dose additive model. Nonetheless, as
discussed in section IV, dose additive
models are not the most biologically
plausible approach if the compounds do
not have the same mode of toxicologic
action. Consequently, depending on the
nature of the risk assessment and the
available information on modes of
action and patterns of joint action, the
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Federal Register / Vol.. 51. Np. 185 /Wednesday.'September'24. 1986 / Notices 34010
most reasonable additive model should
be used.
1. Systemic Toxicants. For systemic
toxicants, the current risk assessment
methodology used by the Agency for
single compounds most often results in
the 'derivation of an exposure level
which is not anticipated to cause
significHnt adverse effects. Depending
on the route of exposure, media of
concern, and the legislative mandate
guiding the risk assessments, these
exposure levels may be expressed In a
variety of ways such as acceptable daily
intakes (ADIs) or reference doses
(UfDs). levels associated with various
margins of safety (MOS), or acceptable
concentrations in various media. For the
purpose of this discussion, the term
"acceptable level" (AL) will be used to
indicate any such crileri- or advisories
derived by the Agency. Levels of
exposure (E) will be estimates obtained
following the mosi current Agsncy
Guidelines for Estimating Exposures
(U.S. EPA. 1930d). For such estimates,
the "hazard index" (HI) of a mixture
based on the assumption of dose
addition may be defined ssr
r. . . +E./AL, (11-1)
where:
E, = exposure level to the ilh toxicant* and
ALi=maximum acceptable level for the iu
toxicant.
Since the assumption of dose addition is
most p'-.^perly applied to compounds
that induce the same effect by similar
modes of action, a separate hazard
index should be generated for each end. .
point (if concern. Dose addition for
dissimilar effects does not have strong
scientific support, and, if done, should
be justified on a case-by-case basis in
terms of biological plausibility.
The assumption of dose addition in
most clearly justified when the
mechanisms of action of the compounds
under consideration are known to be the
same. Since the mechanisms of action
for most compounds are not well
understood, the justification of the
assumption of dose addition will often
be limited to similarities in
pharmacokinclic and toxicologic
characteristics. In any event, if a hazard
index is generated, the quality of the
experimental evidence supporting the
assumption of dose addition must be
clearly articulated.
The hazard index provides a rough
measure of likely toxicity and requires
cautious interpretation. The hazard
index is only a numerical indication of
the nearness to acceptable limits of
exposure or UIH degree to which
acceptable exposure levels are
exceeded. As this Index approaches
unity, concern for the potential hazard
of the mixture increases. If the index
exceeds unity, the concern is the same
as if an individual chemicpl exposure
exceeded Its acceptable level by the
same proportion. The hazard index does
not define dose-response relationships,
and Its numerical value should not be
construed to be a direct estimate of risk.
Nonetheless, If sufficient data are
available to derive Individual
acceptable levels for a spectrum of
effects (e.g., MFO induction, minimal
effects !n several organs, reproductive
effects, and behavioral effects), the
hazard index may suggest what types of
effects might be expected from the
mixture exposure. If the components'
variabilities of the acceptable levels arc
known, or if the acceptable levels are
given as ranges (e.g., associated with
different margins of safety), then the
hazard index should be presented with
corresponding estimates of variation or
range.
Most studies on systemic toxicity
report only descriptions of the effects in
each dose group. If dose-response
curves are estimated for systemic
toxicants, however, dose-additive or
response-additive assumptions can be
used, with preference given to the ir.v>st
biologically plausible assumption (see
section IV for the mathematical details).
2. Carcinogens. For carcinogens,
whenever linearity of the individual
doserr_espon5ej;uryjEs.has bne,n assjurned
(usually restricted to low doses), the
increase in risk P (also called excess or
incremental risk), caused by exposure d,
is related to carcinogenic potency B. as:
P=dB
(II-2)
For multiple compounds, this equation
may be generalized to:
P=Xd,B,
* See the Agcucy'i guideline (U.S. EPA. 190rtd)
for informBlion on how to estimate this value.
This equation assumes independence of
action by the several carcinogens and is
equivalp.nt to the aosumption of dose
addition as well as to response addition
with completely negative correlation of
tolerance, as long as P < 1 (see section
IV). Analogous to the procedure used in
equation II-l for systemic toxicants, an
index for n carcinogens can be
developed by dividing exposure levels
(E) by doses (DR) associated with a set
level of risk:
H1 = E,/DR, + E,/DR,+. . .+E./DR. (H-4)
Note that the less linear the dose-
response curve is, the less appropriate
equations II-3 and II-4 will be, perhaps
even at low doses. It should be
emphasized that because of the
uncertainties in estimating dose-
response relationships for single
compounds, and the additional
uncertainties in combining the
individual estimate to assess response
from exposure to mixtures, response
rates ant? hazard indices may hava merit
in comparing risks but should net be
regarded as measures of absolute risk.
3. Interactions. None of Ihe above
equations Incorporates any form of
synerglstic 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 subchronlc or chronic hazard and Us
suitability for quantitatively altering tho
risk assessment.
For example, if chronic or subchronic
toxicity or carcinogenlclty studies have
been conducted that permit a
quantitative estimation of Interaction for
two chemicals, then It may be desirable
to consider using equations detailed in
section IV, or modifications of these
equations,.to treat ths two compounds
as a single toxicant with greater or
lesser potency than would be predicted
from additivity. Other coraponentb i
the mixture, on which no such
interaction data are available, coulrt
then be separately treated in an additive
manner. Ucfore such n procedure is
adopted, howevsr, a discussion should
be presented of the likelihood that other
compounds in the mixture may interfere
with the interaction of the two toxicants
.. on. which .quantitative .interaction dale
are available. If the weight of evidence
suggests that interference is likely, then
a quantitative alteration of the risk
assessment rt.ay not be justified. In such
casec, the risk assessment may only
indicate the likely nature of interaction^
either synergistic or antagonistic, and
not quantify their magnitudes.
Other types ofinformati.on, such as
•.hose relating 10 mechanisms of toxicant
interaction, or quantitative estimates of
interaction between two chemicals
derived from acute studies, are even less
likely to be of use In the quantitative
assessment of long-term health risks.
Usually it will be appropriate only to
discuss these types of Information,
Indicate the relevance of the Information
to subchronic or chronic exposure, and
indicate, if possible, the nature of
potential interactions, without
attempting to quantify their magnitudes.
When the interactions are expected to
have a minor influence on the mixture's
toxicity, the assessment should Indicate,
when possible, the compounds most
responsible for the predicted toxicity.
This judgment should be based on
predicted toxicity of each component.
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34020 Federal Register / Vol. 51. No; 185 / Wednesday. September 24. 1988 / Notices
based on exposure and toxic or
carcinogenic potential. This potential
alone should not be used as an indicator
of the chemicals posing the most hazard.
4. Uncertainties. For each risk
assessment the uncertainties should be
clearly discussed and the overall quality
of the risk assessment should be
characterized. The scheme outlined in
Table 2 should be used to express the
degree of confidence in the quality of
the data on interaction, health effects.
and exposure.
a. Henlth Effects—In some cases,
when ht-alth effects data are incomplete,
it may bo possible to argue by analogy
or quantitative structure-activity
relatiomihipa that the compounds on
which no health effectii data are
available are not likely to significantly
affect the toxicity of trie mixture, if a
risk assessment includes such an
argument, the limitations of the
approach must ha clearly articulated.
Since a methodology has not been
adopted for estimating an acceptable
level (e.j(., ADI) or carcinogenic
potential for single compounds based
either on quantitative structure-activity
relationships or on the results of short-
term screening tests, such methods are
not at present recommended as th« sole
basis of a risk assessment on chemical
mixtures.
b. Exposure Uncertainties—The
general uncertainties in exposure
assessment have been addressed in the
Agency's Guidelines for Estimating
. J^o.sures.(U.S. EPA, 19S0d). The risk . -
assessor should discuss these exposure
uncertainties in terms of the strength of
the evidence used to quantify the
exposure. When appropriate, the
assessor should also compare
monitoring and modeling data and
discuss any inconsistencies as a source
of uncertainty. For mixtures, these
uncertainties may be increased as the
number of compounds of concern
increases.
If levels of exposure to certain
compounds known to be in the mixture
are not available, but information on
health effects and environmental
persistence and transport suggest that
Jhes^ compounds are not likely to be
significant in affecting the toxicity of the
mixture, then a risk assessment can be
conducted based on the remaining
compounds in the mixture, with
appropriate caveats. If such an argument
cannot be supported, no final risk
assessment can be performed until
adequate monitoring data are available.
As an interim procedure, a risk
assessment may be conducted for those
components in the mixture for which
adequate exposure and health effects
data are available. If the interim risk
assessment does not suggest a hazard,
there ia still concern about the risk from
such a mixture because not all
components in the mixture have been
considered.
c. Uncertainties Regarding
Composition of the Mixture—In perhaps
a worst case scenario, information may
be lacking not only on health effects and
levels of exposure, but also on the
identity of some components of the
mixture. Analogous to the procedure
described in the previous paragraph, an
interim risk assessment can be
conducted on those components of the
mixture for which adequate health
effects and exposure Information are
available. If the risk is considered
unacceptable, a conservative approach
is to present the quantitativa estimates
of risk, along with appropriate
qualifications regarding the
incompleteness of the data. If no hazard
is Indicated by this partial assessment,
the riok assessment should not be
quantified until better health effects and
monitoring data are available to
adequately characterize the mixture
exposure and potential hazards.
///. Assumptions and Limitations
A. Information on Interactions
Most of the data available on toxicant
interactions are derived from acute
toxicity studies using experimental
animals in which mixtures of tv/o
compounds were tested, often in onjy_a
single combination. Major areas of
uncertainty with the use of such data
involve the appropriateness of
interaction data from an acute toxicity
study for quantitatively altering a risk
assessment for subchronic or chronic
exposure, the appropriateness of
interaction data on two component
mixtures for quantitatively altering a
risk assessment on a mixture of several
compounds, and the accuracy of
interaction data on experimental
animals for quantitatively predicting
interactions in humans.
The use of interaction data from acute
toxicity studies to assess the potential
interactions on chronic exposure is
highly questionable unless the
mechanism(s) of the interaction on acute
exposure were known to apply to low-
dose chronic exposure. Most known
biological mechanisms for toxicant
interactions, however, involve some
form of competition between the
chemicals or phenomena involving
saturation of a receptor site or metabolic
pathway. As the doses of the toxicants
are decreased, it is likely that these
mechanisms either no longer will exert a
significant effect or will be decreased to
an extent that cannot be measured or
approximated.
The use of information from two^
component mixtures to assess the
interactions in a mixture containing
mere than two compounds also is
questionable from a mechanistic
perspective. For example. If two
compounds are known to interact, either
cynergistically or antagonistically.
because of the effects of one compound
on the metabolism or excretion of the
other, the addition of a third compound
which either chemically alters or affects
the absorption of one of the first two
compounds could substantially alter the
degree of the toxicologlc interaction.
Usually, detailed studios quantifying
toxicant interactions are not available
on multicomponont mixtures, and the
few studies that are available on such
mixtures (e.g., Gullino et a!., 1958) do not
provide sufficient information to assess
the effects of interactive interference.'
Concerns with the use of interaction
data on experimental mammals to
assess interactions in humans i.? based
on the increasing appreciation for
systematic differences among species in
their response to individual chemicals. If
systematic differences in toxic
sensitivity to single chemicals exist
among species, then it seems reasonable
to suggest that the magnitude of toxicant
interactions among species also may
vary In a systematic manner.
Consequently, even if excellent chronic
data are.availabLe.jQnJthje-Diagnitude.of.,
toxicant interactions in a species of
experimental mammal, there is
uncertainty that the magnitude of the
interaction will be the same in humans.
Again, data are not available to properly
assess the significance of this
uncertainty.
Last, it should be emphasized that
none of the models for toxicant
interaction can predict the magnitude of
toxicant interactions in the absence of
extensive data. If sufficient data are
available to estimate interaction
coefficients as described in section IV,
then the magnitude of the toxicant
interactions for .various proportions of
the same components can be predicted.
The availability of an interaction ratio
(observed response divided by predicted
response) is useful only in assessing the
magnitude of the toxicant interaction for
the specific proportions of the mixture
which was used to generate the
interaction ratio.
The basic assumption in the
recommended approach is that ilsk
assessments on chemical mixtures are
best conducted using toxicologic data on
the mixture of concern or a reasonably
similar mixture. While such risk
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Federal Register / Vol. 5X No. 185 / Wednesday. September 24. 1986 / Notices
34021
assessments do not formally consider
to.xicologic interactions as part of a
mathematical model,It is assumed that
responses in experimental mammals or
human populations noted after exposure
to the chemical mixture can be used to
conduct risk assessments on human
populations. In bioassays of chemical
mixtures using experimental mammals,
the same limitations inherent in species-
to-species extrapolation for single
compounds npply io mixtures. When
using health effects data on chemical
mixtures from studies on exposed
human populations, the limitations of
cpidemiologic studies in the risk
assessment of single compounds also
npply to mixtures. Additional limitations
mny be involved when using health
effects data on chemical mixtures if the
components in (he mixture are not
conslnnt or if the components partition
in the environment.
D. Addilivlly Models
If sufficient data are not available on
the effects of the chemical mixture of
concern or a reasonably similar mixture,
the proposed approach is to assume
additivily. Dose additivity is based on
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 acceptable levels, which, as currently
defined, cannot be adapted to the
different forms of response additivity as
described in section IV.**"-
Additivity models can be modified to
incorporate quantitative data on
toxicant interactions from subchronic or
chroni- studies using the models given
in section IV or modifications of those
models. If this approach is taken,
however, it will be under the assumption
that other components in the mixture do
not interfere with the measured
interaction. In practice, such subchronic
or chronic interactions data seldom will
be available. Consequently, most risk
assessments (on mixtures) will be based
on an assumption of additivity. as long
as the components elicit similar effects.
Dose-additive and response-additive
assumptions can lead to substantial
errors in risk estimates if synergistic or
antagonistic interactions occur.
Although dose additivity has been
shown to predict the acute toxicities of
many mixtures of similar and dissimilar
compounds (e.g., Pozzani et al., 1959;
Smyth et al.. 1909,1970; Murphy, 1980),
some marked exceptions have been
noted. For example, Smyth et al. (1970)
tested the interaction of S3 pairs of
industrial chemicals based on acute
lethality in rats. For most pairs of
compounds, the ratio of t!«j predicted
LDM to observed LDM did not vary by
more than a factor of 2. The greatest
variation was seen with an equivolume
mixture of morpholine and toluene, in
which the observed LDM was about
fives times less than the LDH predicted
by dose addition. In a study by
Hammond et al. (1979). the relative risk
of lung cancer attributable to smoking
was 11. while the relativb risk
associated with asbestos exposure was
5. The relative risk of lung cancer from
both smoking and asbestos exposure
was 53, indicating a substantial
synergistic effect. Consequently, in some
cases, additivity assumptions may
substantially underestimate risk. In
other cases, risk may be overestimated.
While this is certainly an unsatisfactory
situation, the available data on mixtures
are insufficient for estimating the
magnitude of these errors. Based on
current information, additivity
assumptions are expected to yield
generally neutral risk estimates (i.e.,
neither conservative nor lenient) and are
plausible for component compounds that
Induce similar types of effects at the
same sites of action.
IV. Mathematical Models and the
Measurement of Joint Action
The simplest mathematical models for
Joint action assume no interaction in
any mathematical sense. They describe
either dose addition or response
addition and are motivated by data on
acute lethal-effects 'of mixtures of Two
compounds.
A. Dose Addition
Dose addition assumes that the
toxicants in a mixture behave as If they
were dilutions or concentrations of each
other, thus the tr;u slopes of the dose-
response curves for the individual
compounds are identical, and the
response elicited by the mixture can be
predicted by summing the Individual
doses after adjusting for differences in
potency; this is defined as the ratio of
equitoxic doses. Probit transformation
typically makes this ratio constant at all
doses when parallel straight lines are
obtained. Although this assumption can
be applied to any model (e.g.. the one-hit
model in NRC. 1980b). it has been most
often used in toxicology with the log-
dose probit response model, which will
be used to illustrate the assumption of
close addition. Suppose the*, two
toxicants show the following log-dose
probit response equations:
Y,=
Y,=
=0.3+3 log Zi
:1.2+3logZ,
(IV-1)
(IV-2)
where Yj is the probit response
associated with a dose of Z, (1=1, 2).
The potency, p, of toxicant #2 with
respect to toxicant #1 is defined by the
quantity Zi/Z, when Y,=Y, (that is
what is meant by equitoxic doses). In
this example, the potency, p. Is
approximately 2. Dose addition assumes
that the response. Y. to any mixture of
these two toxicants can be predicted by;
Y«=0.3+3log(Zi+pZt) (IV-3)
Thus, since p is defined as Z,/Z,,
equation IV-3 essentially converts Z,
into an equivalent dose of Z, by
adjusting for the difference In potenay.
A more generalized form of this
equation for any nupber of toxicants in:
Y-a, + blog(f,+ .
where:
a,— the y-intercept of the dose-response
equation for toxicant #1
b = the »lope of the dose-response linos for
the toxicants
f,»the proportion of the I" toxicant In the
mixture
Pi—the potency of the I"1 toxicant with
respect to toxicant #1 (I.e.. Z,/Z,). and
Z=the sum of the Individual doses In the
mixture.
A more detailed discussion of the
derivation of the equations for dose
addition Is presented by Finney (1971).
B. Response Addition
The other form of additivity is
referred to as response addition. As
detailed by Bliss (1939), this type of joint
action assumes that the two toxicants
act on different receptor systems and
that the correlatibn'of individual
tolerances may range from completely
negative (r=—1) to completely positive
(r= +1). Response addition assumes
that the response to a given
concentration of a mixture of toxicants
is completely determined by the
responses to the components and the
pairwise correlation coefficient. Taking
P as the proportion of organisms
responding to a mixture of two toxicants
which evoke Individual responses of P,
and P,, then
P=P, lfr=landP,>P,
P=P, lfr=landP,
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34022
Federal Register / Vol. 61, No. 185 / Wednesday, September 24, 1S88 / Notices
following modification of equation IV-4
for dose addition:
Y = a,+b log (f.+pf.+K [pf,f,]ci]+b log Z
(IV-o)
where a,. b. fu f,. p. and Z are defined as
before, und K is the coefficient of
interaction. A positive value of K
indicates synergism. a negative value
indicates antagonism, and a value of
zero corresponds to dose addition as In
equation IV-4. Like other proposed
modifications of dose addition (Hewlett.
1909), the equation assumes a consistent
interaction throughout the entire range
of proportions of individual components.
To account for such asymmetric patterns
of interaction as those observed by
Alstott <;t al. (1973). Durldn (1981)
proposed the following n.jdification to
equation IV-6:
Y-a.-i-b log (r,4pf«+K1f,(Pf,f,]»'+K,r,
(pf.f^l + blogZ (IV-10)
In which Kf.pf.f,)" is divided into two
components, K,f,(pf1f,)0-«nnd KJ,(pf,f,)
". Since Kt and Ki need not have the
same sign, apparent instances of
antagonism at one receptor site and
synergism at another receptor site can
be estimated. When K, and K. are equal,
equation 1V-10 reduces to Equation
IV-9.
It should be noted that to obtain a
reasonable number of degrees of
freedom in the estimation of K in
equation IV-9 or K, and K, in equation
IV-10, trie toxicity of several different
combinations of the two components
'must be assayed along with assays of
..ihe.toxiclty of the individual •
components. Since this requires
experiments with large numbers of
animals, such analyses have been
restricted for the most part to data from
acute bioassays using insects (e.g..
Finney, 1971) or aquatic organisms
(Durkin, 1979). Also, because of the
complexity of experimental design and
the need for large numbers of animals,
neither equation IV-6 nor equation IV-
10 has been generalized or applied to
mixtures of more than two toxicants.
Modifications of response-additive
models to include interactive terms have
also been proposed, along with
appropriate statistical tests for the
assumption of additivity (Korn and Liu,
1983: Wahrendorf et al.. 1981).
In the epidemlologic literature.
measurements of the extent of toxicant
interactions. S. can be expressed as the
ratio of observed relative risk to relative
risk predicted by some form of
additivity assumption. Analogous to the
ratio of interaction in classical
toxiocology studies. S = 1 indicates no
interaction. S>1 indicates synergism.
and S<1 indicates anagonism. Several
models for both additive and
multiplicative risks have been proposed
(e.g.. Hogan et al.. 1978; NRG, 1980b;
Walter, 197B). For instance, Rothman
(1978] has discussed the use of the
following measurement of toxicant
interaction based on the assumption of
risk additivity:
) (IV-ll)
where Rw is the relative risk from
compound #1 in the absence of
compound #2. R., is the relative risk
from compound #2 in the absence of
compound #1, and Ru is the relative risk
from exposure to both compounds. A
multiplicative risk model adapted from
Walter and Holford (1978, equation 4)
can be stated as:
8 - Ru/(R,.R,,)
(IV-12)
As discussed by both Walter and
Holford (1973) and Rothman (1976). the
risk-additive model is generally applied
to agents causing diseases while the
multiplicative model is more appropriate
to agents that prevent disease. The
relative merits of these and other
indices have been the subject of
considerable discussion in the
epidemiologic literature (Hpgan et al..
1978: Kupper and Hogan. 1978; Rothman.
1978: Rothman et al., 1980; Walter and
Holford, 1978). There seems to be a
consensus that for public health
concerns regarding causative (toxic)
agents, the additive model is more
appropriate.
Both the additive and multiplicative
. models assume statistical independence
in that the risk associated with exposure
to both compounds in combination can
be predicted by the risks associated
with separate exposure to the individual
compounds. As illustrated by
Siemlatycki and Thomas (1981) for
multistage carcinogeneais, the better
fitting statistical model will depend not
only upon actual biological Interactions.
but also upon the stages of the disease
process which the compounds affect.
Consequently, there is no a priori basis
for selecting either type of model in a
risk assessment. As discussed by Stara
et al. (1983). the concepts of multistage
carcinogenesls and the effects of
promoters and cocarcinogens on risk are
extremely complex issues. Although risk
models for promoters have been
proposed (e.g., Burns et al., 1983), no
single approach can be recommended at
this time.
V. Reference!
ACGIH (American Conference of
Governmental Industrial Hygienists). 1983.
TLVs: threshold limit values for chemical
substances and physical agents in the work
environment with intended changes for
1983-1884. Cincinnati, OH. p. 68.
Alstott RJ-, MJJ. Tarranf, and R.B. Forney.
197$. The acute toxldties of 1-
methybcanthine, ethanol. and 1-
methylxanthine/ethanol combinations in
the mouse. ToxicoL Appl. PharmacoL
24:3!»-404.
Blist, C.L 1039. The toxicity of poisons
applied jointly. Ann. Appl. Biol. 28:585-615.
Burnt, FM R. Albert, E. Altschuler, and E,
Morris. 1983. Approach to risk assessment
for jjenotoxic carcinogens based on data
from the mouse skin initiation-promotion
model. Environ. Health Perspect. 50:309-
320.
Durkin. P.R. 1979. Spent chlorlnatlon liquor
and chlorophenollcs: a study In
detoxicatlon and Joint action using
Daphnta magnet. PhfD. Thesis. Syracuse.
NY: State University of New York College
of Environmental Science and Forestry, p
145.
Durkin. P.R. 1P81. An approach to the
analysis of toxicant Interactions In the
aquatic environment. Proceedings of the
4th Annual Symposium on Aquatic
Toxicology. American Society for Testing
• and Materials, p. 388-401.
Finnoy. D.J. 1942. The analysis of toxicity
tests on mixtures of poisons. Ann. Appl.
Biol. 29:82-94.
Finney. D.J. 1971. Problt analysis. 3rd ed.
Cambridge, Great Britain: Cambridge
University Press, 333 p.
Goldstein. A.. L. Aronow. and S.M. Kalman.
1974. Principles of drug action: the basis of
pharmacology, 2nd ed. New York, NY: John
Wiley and Sons. Inc.. 854 p.
GuHtno. P., M. Winltz. S.M. Birnbaum. J.
Cornfield, M.C. Otey. and J.P. Greenstein.
1958. Studies on the metabolism of amlno
acids and related compounds in vivo. I.
.. Toxicity of essential amlno-aelds.
individually and In mixtures, and the
protective effect of L-arglnlne. Arch.
Biochem. Blophys. 54:319-332.
Hammond. E.C.. I.V. Sellkoff. and H.
Seidman. 1979. Asbestos exposure.
cigarette smoking and death rates. Ann. NY
Acad. Scl. 330:473-490.
Hewlett, P.S. 1969. Measurement of the
potencies of drug mixtures. Biometrics
25:477-187.
Hogan, M.D., L. Kupper, B. Most, and J.
Haseman. 1978. Alternative approaches to
Rothman's approach for assessing
synerglsm {or antagonism) In cohort
studies. Am. J. Epldemlol. 108(l):60-67.
Klaassen. C.D.. and J. Doull. 1980. Evaluation
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Doull. C.D. Klaassen. and M.O. Amdur. eds.
Toxicology: the basic science of poisons.
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Korn, E.L., and P-Y. Liu. 1983. Interactive
effects of mixtures of stimuli in life table .
analysis. Biometrika. 70:103-110.
Kupper. L, and M.D. Hogan. 1978. Interaction
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Levine, R.E. 1973. Pharmacology: drug actions
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and Company, 412 p.
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Murphy, S.D. 1980. Assessment of the-
potential for toxic interactions among
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S.D. Murphy, and R. Pnoletti. eds. The
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p. 27-28.
NRC (National Research Council). 1980b.
Principles of lexicological interactions
associated with multiple chemical
exposures. Washington, DC: National
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OSHA (Occupational Safety and Health
Administration). 1983. General Industry
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Substnnces. Code of Federal Regulations.
40:1810.1000 (d)(2)(I). Chapter XVII—
Occupational Safety and Health
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Plackctt. R.L. and P.S. Hewlett. 1948.
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Pozznni. U.C.. C.S. Well, and C.P. Carpenter.
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valuns: 5. The experimental inhalation of
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relationship between single dose inhalation
and single dose ora! data. Am. Ind. Hyg.
Asaoc. J. 20:304-369.
Rothman. K. 1976. The estimation of synergy
or antagonism. Am. J. Epidemiol. 103(5):
500-511.
Rolhmiin, K. 1978. Estimation versus
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Rothman. K., S. Greenland, and A. Walker.
1980. Concepts of interaction. Am. J.
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Siemialycki. J.. and D.C. Thomas. 1981.
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387.
Smyth. H.F.. C.S. Weil. J.S. West, and C.P.
Carpenter. 1909. An exploration of joint
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Smyth. H.F.. C.S. Weil. J.S. West and C.P.
Curpenter. 1970. An exploration of joint
toxic action. II. Equiloxic versus
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Pharmncol. 17:498-503.
Slnra. J.F.. D. Mukerjee. R. McGaughy. P.
Durkin, and M.L. Dourson. 1983. The
current use of studies on promoters and
cocarcinogens in quantitative risk
asse.'isment. Environ. Health Perspecl.
50:359-308.'
U.S. EPA. 1986a. Guidelines for carcinogen
risk assessment. Federal Register.
U.S. ETA. 1988b. Guidelines for mutagenicity
risk assessment. Federal Register.
U.S. EPA. 1986c. Guidelines for the health
assessment of developmental toxicants.
Federal Register.
U.S. EI'A. 1980d. Guidelines for estimating
exposures. Federal Register.
Veldstra, H. 1956. Synergism and potentiation
with special reference to the combination
of sli-uctural analogues. Pharmacol. Rev.
8:330-387.
Wahrendorf, J., R. Zentgrof. and C.C. Brown.
1981. Optimal designs for the analyils of
interactive effects of two carcinogens or
other toxicants. Biometrics. 37:45-R4.
Waltar, S.D. 1976. The estimation end
interpretation of attributable risk in health
research. Biometrics. 32:829-849.
Walter, S.D., and T.R. Holford. 1978.
Additive, multiplicative, and other models
for disease risks. Am. J. EpldemloL 108:341-
346.
Withey. J.R. 1981. Toxicodynamlcs and
biotransformation. In: International
Workshop on the Assessment of
Multlch'emical Contamination. Milan, Italy.
(Draft copy courtesy of JJi. Withey)
WHO (World Health Organization). 1981.
Health effects of combined exposures In
the work environment. WHO Tech. Rayort
Series No. 602.
Part B. Response to Public and Science
Advisory Board Comments
/. Introduction
This section summarizes some of the
major issues raised In public comments
on the Proposed Guidelines for the
Health Risk Assessment of Chemical
Mixtures published on January 9.1985
(50 FR 1170). Comments were lecelved
from 14 individuals or organizations. An
issue paper reflecting public and
external review comments was
presented to the Chemical Mixtures
Guidelines Panel of the Science
Advisory Board (SAB) on March 4,1985.
At its April 22-23,1985, meeting, the
SAB Panel provided the Agency with
additional suggestions and
recommendations concerning the
Guidelines." ThisVection also
summarizes the issues raised by the
SAB.
The SAB and public commentors
expressed diverse opinions and
addressed issues from a variety of
perspectives. In response to comments,
the Agency has modified or clarified
many sections of the Guidelines, and is
planning to develop a technical support
document in line with the SAB
recommendations. The discussion that
follows highlights significant Issues
raised in the comments, and the
Agency's response to them. Also, many
minor recommendations, which do not
warrant discussion here, were adopted
by the Agency.
//. Recommended Procedures
A. Definitions
Several comments were received.
concerning the lack of definitions for
certain key items and the general
understandability of certain sections.
Definitions have been rewritten for
several terms and the text has been
significantly rewritten to clarify the
Agency's intent and meaning.
Several commenlors noted the lack of
a precise definition of "mixture," even
though several classes of mixtures are
discussed. .In the field of chemistry, the
term "mixture" is usually differentiated
from true solutions, with the former
defined as nonhomogencous
multicomponent systems. For these
Guidelines, the term "mixture" is
defined as ". . . any combination of two
or more chemicals regardless of spatial
or temporal homogeneity of source"
(section 1). These Guidelines are
intended to cover risk assessments for
any situation where the population Is
exposed or potentially exposed to two
or more compound's of concern.
Consequently, the introduction has been
revised to clarify the intended breudth
of application.
Several commentors expressed
concern that "sufficient similarity" was
difficult to define and that the
Guidelines should give more details
concerning similar mixtures. The
Agency agrees end is planning research
projects to improve on the definition.
Characteristics such as composition and
toxic end-effects are certainly
important, but the best indicators of
similarity in terms of risk assessment
have yet to be determined. The
discussion in the Guidelines emphasizes
case-by-case judgment until the
necessary research can be performed.
The Agency considered but rejected
adding an example, because it is not
likely that any single example would be
adequate to illustrate the variety in the
data and types of judgments that will be
required in applying this concept.
Inclusion of examples is being
considered for the technical support
document.
B. Mixtures of Carcinogens and
Systemic Toxicants
The applicability of trie-preferred
approach for a mixture of carcinogens
and systemic (noncarclnogenic)
toxicants was a concern of several
public commentors as well as the SAB.
The Agency realizes that the preferred
approach of uslr^ test data on the
mixture Itself may not be sufficiently
protective in all cases. For example,
take a simple two-component mixture of
one cardnogtm and one toxicant.' The
preferred approach would lead to using
toxicity data on the mixture of the two
compounds. However, It Is possible to
set the proportions of each component
so that in a chronic bioassay of such a
mixture, the presence of the toxicant
could mask the activity of the
carcinogen. That is to say, at doses of
the mixture sufficient for the carcinogen
to induce tumors in the small
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experimental group,:the toxicant could
Induce mortality. At a lower dose In the
same study, no adverse effects would be
observed, Including no carcinogenic
"effects. The data would, then suggest use
of a threshold approach. Since
carclnogenicity Is considered by the
Agency to.be a honthresriold effect. It
may not be prudent to construe the
negative results of such a bibassay as
Indicating the absence of risk at lower
doses. Consequently, the Agency has
revised the discussion of the preferred
approach to allow the risk assessor to
.evaluate the potential for masking of
• carclno'flenlcity or other effects on a
case-by-case basis.
Another difficulty occurs with such a
mixture when the risk assessment needs
to be based on data for the mixture
components. Carcinogens and systemic
toxicants are evaluated by the Agency
•using different approaches and generally
arc described by different types of data:
respbnne rales'for carcinogens vs. effect
;,. descriptions for toxicants. The Agency
recognizes this difficulty and
recommends research to develop a new
• assessment model for combining these
"dissimilar data sets Into one risk
estimate. One suggestion In the interim
' is to present'separate risk estimates for
the'.dis similar end points. Including
• carcinogenic, teratogenic, routagenic,
and systemic toxicant components.
///. Additivity Assumption
Numerous comments were received
'concerning the assumption of additivity.
including:
a. the applicability of additivity to
"complex" mixtures;
b. the use of dose additivity for
compounds that induce different effects;
c. the intepretation of the Hazard
Index: and
d. the use of interaction data.
Parts of the discussion in the proposed
guidelines concerning the use of
addilivity assumptions were vague and
have been revised in the final
Guidelines to clarify the Agency's Intent
and position.
A. Complex Mixtures
The issue of the applicability of an
assumption of additivity to complex
mixtures containing tens or hundreds of
components was raised In several of the
public comments. The Agency and its
reviewers agree that as the number of
.compounds in the mixture increases, an
assumption of additivity will become
less reliable in estimating risk-This is
based on the fact that each component
estimate of risk or an acceptable level is
associated with some error and
uncertainty. With current knowledge,
the uncertainty will increase as the
number of components Increases. In any
event, little experimental data fire
available to determine the general
change in the error as the mixture
contains more components. The Agency
has decided that a limit to the number of
components should not be set in these
Guidelines. However, the Guidelines do
explicitly state that as the number of
compounds in the mixture increases, the
uncertainty associated with the risk
assessment is also likely to Increase.
B. Dose Additivity
Commentor* were concerned about
what appeared to be a recommendation
of the use of dose additivity for
compounds that induct) different effects.
The discussion following the dose
additivity equation was clarified to
indicate that the act of combining all
compounds, even if they induce
dissimilar effects, la a screening
procedure and not the preferred
procedure in developing a hazard Index.
The Guidelines were further clarified to
state that dose (or response) additivity
is theoretically sound, and therefore
best applied for assessing mixtures of
similar acting components that do not
interact.
C. Interpretation of the Hazard Index
Several comments addressed the
potential for misinterpretation of the
hazard Index, and some questioned its
validity, suggesting that it mixes science
and value judgments by using
"acceptable" levels in the calculation.
The Agency agrees with the possible
confusion regarding its use and has
revised the Guidelines for clarification.
The hazard index is an easily derived
restatement of dose addilivity, and Is,
therefore, most accurate when used with
mixture components that have similar
toxic action. When used with
components of unknown or dissimilar
action, the hazard index is less accurate
and should be interpreted only as a
rough Indication of concern. As with
dose addition, the uncertainty
associated with the hazard Index
Increases as the number of components
Increases, so that It Is less appropriate
for evaluating the toxlclty of complex
mixtures.
D. Use of Interaction Data
A few commentors suggested that any
Interaction data should be used to
quantitatively alter the risk assessment.
The Agency disagrees. The. current
information on interactions is meager,
with only a few studies comparing
response to the mixture with that
predicted by studies on components.
Additional uncertainties include
exposure variations due to changes in
composition, mixture dose, and species
differences in the extent of the
interaction. The Agency is constructing
an Interaction :data base in an attempt to
answer some of these issues. Other
comments concerned the use of different
types of interaction data. The Guidelines
restrict the use of Interaction data to
that obtained from whole animal .
bloassays of a duration appropriate to
the risk assessment. Since such data are
frequently lacking, at least for chronic or
subchronic effects, the issue is whether
to allow for ths use of other Information
such as acute date. In vitro data, or
structure-activity relationships to *
quantitatively alter the risk assessment,
perhaps by use of a safety factor. The
Agency believes that sufficient scientific
support does not exist for the use of
such data in any but a qualitative
discussion of possible synorgistic or
antagonistic effects.
IV. Uncertainties and the Sufficiency of
the Data Base
In the last two paragraphs of section II
of the .Guidelines, situations are
discussed In which the risk assessor is
presented with Incomplete toxiclty.
• monitoring, or exposure data. The SAB.
as well as several public commentors,
recommended that the "risk
management" tone of this section be
modified and that the option of the risk
assessor to decline to conduct a risk
assessment be made more explicit.
This is a difficult issue that must
consider not only the quality of the
available data for risk assessment, but
also the needs of the Agency in risk
management. Given the types of poor
data often available, the risk assessor
may indicate that the risk assessment is
based on limited information and thus
contains no quantification of risk.
Nonetheless, in any risk assessment,
substantial uncertainties exist. It is the
obligation of the risk assessor to provide
an assessment, but also to ensure that
all the assumptions and uncertainties
are articulated clearly and quantified
whenever possible.
The SAB.artlculated several o'her
recommendations related to
uncertainties, all of which have been
followed in the revision of the.
Guidelines. One recommendation was
that the summary procedure table also
be presented as a flow chart so that all
options are clearly displayed. The SAB
further recommended the development
of a system to express the level of
confidence in the various steps of the
risk assessment.
The Agency has revised the summary
table to present four major options: risk
assessment using data on the mixture
['
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34025
itself, data on a similar mixture, data on
the mixture's components, or declining
to quantify the risk when the data are
inadequate. A flow chart of this table
has also been added to more clearly
depict the various options and to suggest
the combining of the several options to
indicate the variability and uncertainties
in the risk assessment.
To determine the adequacy of the
data, the SAD also recommended the
development of a system to express the
level of confidence associated with
various steps In the risk assessment
process. The Agency has developed a
rating scheme to describe data quality in
three areas: interaction, health effects,
and exposure. This classification
provides a range of five levels of data
quality for each of the three areas.
Choosing the last level in any area
results in declining to perform a
quantitative risk assessment due to
inadequate data. These last levels are
described as follows:
Interactions:
An assumption of additivity cannot be
justified, and no quantitative risk
assessment can be conducted.
Health effects:
A lack of health effects information on
the mixture and its components
precludes a quantitative risk
assessment.
Exposure:
The available exposure information is
insufficient for conducting a risk
assessment.
Several commentors. Including the
SAB, emphasized the importance of not
losing these classifications and
uncertainties farther along in the risk
management process. The discussion of
uncertainties has been expanded in the
final Guidelines and Includes the
recommendation that a discussion of
uncertainties and assumptions be
included at every step of the regulatory
process that uses risk assessment.
Another SAB comment was that the
Guidelines should Include additional
procedures for mixtures with more than
one end point or effect. The Agency
agrees that these are concerns and
revised the Guidelines to emphasize
these as additional uncertainties worthy
of further research.
V. Need fora Technical Support
Document
The third major SAB comment
concerned the necessity for a separate
technical support document for these
Guidelines. The SAB pointed out that
the scientific and technical background
from which these Guidelines must draw
their validity Is so broad and varied that
it cannot reasonably be synthesized
within the framework of a brief set of
guidelines. The Agency is developing a
technical support document that will
summarize the available information on
health effects from chemical mixtures,
and on interaction mechanisms, as well
as Identify and develop mathematical
models and statistical techniques to
support these Guidelines. This document
will also identify critical gaps and
research needs.
Several comments addressed the need
for examples on the use of the
Guidelines. The Agency has decided to
include examples in the technical
support document.
Another Issuo raised by the SAB
concerned the identification of research
needs. Because little emphasis has been
placed on the toxicology of mixtures
until recently, the Information on
mixtures Is limited. The SAB pointed out
that Identifying research needs Is critical
to the risk assessment process, and the
EPA should ensure that these needs are
considered in the research planning
process. The Agency will Include a
section in the technical support
document that Identifies research needs
regarding both methodology and data.
[FR Doc. 86-19003 Filed 9-23-88; 8:45 am]
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