ADVANCES IN THE RISK ASSESSMENT GUIDELINES
PRESENTED AT THE SESSION
ADVANCES IN ASSESSMENT, CCTMJNICATiaN AND MANAGING RISKS
34TH ANNIVERSARY TECHNICAL CONFERENCE
MID-ATLANTIC STATES SECTION
AIR POLLUTION CONTROL ASSOCIATION
OCTOBER 21, 1988
ALAN M. EHRLICH, Ph.D.
NOTICE: The views expressed in this paper are those of the author and do not
necessarily reflect the views or policies of the U.S. Environmental
Protection Agency.
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVTJOWENTAL PROTECTION AGENCY
Washington, D.C. 20460
-------
ABSEWCT
In 1986, the Environmental Protection Agency issued five guidelines for
conducting risJc assessments. They describe the process used by EFA to evaluate
the health effects of exposure to environmental toxicants. When those guidelines
were issued, EPA stated its intent to continue the development of new guidelines
and revision of existing guidelines. This paper discusses the seven guideline
activities under way as of October 1988: female reproductive risk, male
reproductive risk, exposure measurements, developmental toxicity, carcinogenicity,
non-cancer health effects, and neurotoxicity.
-------
ADVANCES IN THE RISK ASSESSMENT GUIDELINES
About five yc=ars ago, EPA convened what it called the Toxics Integration Task
Force to investigate the quality and consistency of EFA's risk assessments. The
task force made two key recoimiendations — (1) to establish mechanisms to better
coordinate the risk assessment process, and (2) to develop risk assessment
guidelines. The Risk Assessment Forum and the Risk Assessment Council were
created to meet the first recommendation. Readers of this current paper may have
heard Peter Preuss discuss the first round of guidelines at the 1986 APCA meeting,
or may have read the corresponding paper in JAPCA (Preuss and Ehrlich, 1987).
This current paper will provide what is, in essence, a progess report on the
second round of guidelines.
In order to put these most recent developments in context, however, it will
first be helpful to review briefly the history of the last five years.
The terminology currently used within the Federal government was set out in
1983 in the National Academy of Science's report, Risk Assessment in the Federal
Government: Managing the Process (National Research Council, 1983). In that
report, the NAS recommended separating risk assessment from risk management;
defined risk assessment in terms of its four components of hazard identification,
dose-response assessment, exposure assessment, and risk characterization; and
recommended that agencies develop "inference guidelines" to describe how risk
assessments are done. EPA uses the term "risk assessment guidelines" for its
inference guidelines. We can look at the process as a pair of bridges spanning
the gaps between available information, risk characterization, and regulatory
decision-making. Risk assessment, and the risk assessment guidelines fill the
first gap with a bridge constructed of thinking about the data, organizing the
data, conducting the assessment, and presenting the findings. Then the second gap
is bridged by social, legal, economic, and political considerations. EPA's
guidelines set fort' internal Agency procedures that:
o Promote consistency across EPA risk assessments by using common
approaches to risk assessment
o Promote the quality of the science underlying EPA risk assessments by
thoughtful development of a consensus approach
o Clarify EPA's approach to risk assessment by informing the public and the
regulated community about the process by which the EPA will evaluate
scientific information
Since the guidelines are not regulations, risk assessors outside of EPA are
not obligated to use them. The guidelines are also not fixed, rigid rules within
the Agency; rather, they are standards to guide EPA in conducting its own risk
assessments and in evaluating risk assessments done outside the Agency. That is,
they are flexible to encourage the use of all relevant data and the appropriate
scientific methods and judgments. The guidelines can, however, influence the risk
assessments that underlie EPA regulations by:
o Making EPA's risk assessments more consistent and of higher technical
quality
-------
- 2 -
o Familiarizing risk assessors throughout the country with EFA's approach
o Making it possible for scientists to plan their experiments to collect
the information that EPA scientists would like to have available when
conducting a risk assessment
In developing the guidelines, EFA has used a process which is typical both of
consensus standard development procedures and of administrative procedures. Draft
guidelines are first developed by work groups of Agency scientists representing
all Agency programs. They are then submitted to invited expert review and
internal Agency review that includes the Forum and the Council, and published for
comment both by the public at large and the Agency's Science Advisory Board (SAB);
the two aspects of the public cement process can be accomplished either in
sequence or approxijnately concurrent steps. The guidelines are then revised,
submitted for final Agency review and review where appropriate by other Federal
agencies, and finally issued.
The first five guidelines were proposed in late 1984-early 1985 and issued in
September 1986. They are: Guidelines for Carcinogen Risk Assessment, Guidelines
for Mutagenicity Risk Assessment, Guidelines for the Health Risk Assessment of
Chemical Mixtures, Guidelines for the Health Assessment of Suspect Developmental
Toxicants, and Guidelines for Estimating Exposures. For further details about the
1986 guidelines, the reader is referred either to the guidelines (U.S. EPA, 1986a-
e; 1987) or to papers describing them (e.g., Preuss and Ehrlich, 1987).
When EFA began this Agency-wide guidelines development program, we recognized
several important factors:
o First, that for any one issue, there was not likely to be a single
correct answer, but rather a range of defensible positions the Agency
could take
o Second, that consensus could be reached on some issues in a relatively
short time period, but other issues would take significantly longer, and
o Third, that the guidelines would be evolving documents, needing updates
as the science base relating to risk assessment leads to new
understanding of the effects of toxic substances, or to a reduction of
the uncertainty inherent in the risk assessment process.
Thus, the five guidelines published in 1986 were planned as the first step in an
on-going process of developing new guidelines and amending current ones.
That brings us up to today. At this time, seven guideline projects are
underway: female reproductive risk, male reproductive risk, exposure measurement,
possible developmental toxicity amendments or revisions, neurotoxicity, non-cancer
health effects, and possible carcinogenicity amendments. They are listed
approximately in order of planned completion through 1990, with the first two
already proposed, and the others in various stages of development. Each will be
discussed in the following paragraphs, though not necessarily in this implied
chronological order.
-------
- 3 -
The Proposed Guidelines for Assessing Female Reproductive Risk and for
Assessing Male Reproductive Risk were published on June 30, 1988 (U.S. EPA, I988a,
b). They have been reviewed by the SAB concurrently with the public review. At
the public discussion with the SAB on July 14, the review conmittee expressed its
concurrence with the general thrust of the guidelines, and the concept of effect-
specific guidelines. They made specific suggestions in the areas of the weight-
of-evidence categorization and the dose-response discussion. The Agency is
currently waiting for the SAB's formal comnent letter. In addition, the public
comment period was extended to September 30, 1988 (U.S. EFA, I988c). After all of
the comments have been received, the proposed guidelines will be revised as
appropriate, and then published as final documents.
These risk assessment guidelines are not descriptions of testing protocols as
set out in other Agency publications. Rather, the guidelines supplement the
testing protocols by giving guidance on the organization and evaluation of the
data after test data have been collected. That is, they propose formats for
discussing the issues related to reproductive risk based on the four components of
risk assessment: hazard identification (the most detailed discussion), dose-
response assessment, exposure assessment, and risk characterization.
The Hazard Identification section is "the most detailed in these and other
health-effect specific guidelines. In the female reproductive risk guidelines,
the Hazard Identification section should include a discussion of:
o Laboratory Animal Studies; indices, end points, and their interpretation,
i.e.,
protocol considerations such as
+ use of generational tests and the relatively new continuous
breeding tests,
+ setting appropriate dose ranges,
+ use of controls,
+ selection of test animals,
+ lengths of exposure, and
+ listing of pathological parameters
indices of reproductive toxic ity such as
+ fertility,
+ litter size,
+ alterations during pregnancy or at birth, and
+ offspring survival
-------
- 4 -
consideration of other end points, such as alterations of the female
reproductive system and reproductive organ toxicity
o Human Studies where epidemiological or clinical data exist, especially
where precise measures of exposure are available, including
epidemiological studies
examinations of clusters or case reports
human clinical evaluations
o FharmacoJcinetics
o Comparisons of Molecular Studies
o weight-of-Evidence Determinations (No formal scheme has been proposed,
but there was a request for Garments on possible development and use of a
formal scheme.)
These guidelines refer to the current Agency reference dose (RfD) approach for
dose-response assessment and to the exposure guidelines for exposure assessment.
They also solicited comnents on the applicability of mathematical dose-response
models specific to assessing reproductive risk. The fourth step, Risk
Characterization is the combination of the first three steps into an estimation of
risk, but also including a discussion-of the assumptions, major scientific
judgments, and estimates of uncertainty.
The proposed male reproductive risk guidelines have a similar format. Again,
the Hazard Identification step is the most detailed, and includes consideration
of:
o Laboratory Testing Protocols, i.e.,
types of tests, such as
+ single and multigeneration tests
+ the relatively new continuous breeding protocols
+ dominant lethal tests
"'••* subchronic toxicity tests
* chronic toxicity tests
design factors that may influence test results, such as
+ duration of dosing
+ length of mating period
-------
+ number of females mated to each male
end points of toxicity, e.g.,
+ routinely evaluated ones such as tody weight, organ weights,
pathology, fertility, and pregnancy outcomes
+ supplemental end points such as sperm evaluation or endocrine
evaluations
+ biochemical markers of toxicity
+ paternally mediated postnatal outcomes
+ sexual behavior
o Human Studies
epidemiologic studies
+ general design considerations such as power of the study,
potential bias in data collection, control of other risk
factors—effect modifiers—confounders, and statistical factors
+ selection of outcomes for study, including semen evaluations
and reproductive history studies
+ community studies and surveillance programs
examinations of clusters or case reports
o Pharmacokinetic Considerations (which may be a significant issue because
of the apparent existence of a blood/testis barrier)
o Structure-Activity Relationships
o Weight-of-Evidence Determination
In the male reproductive risk guidelines, a specific weight-of-evidence
categorization and definition of terms has been proposed, as well as sane of the
study considerations that go into making that weight-of-evidence determination.
The weight-of-evidence categorization was one of the areas of comment by the SAB,
and changes, will be considered by the Agency. As proposed, the weight-of-evidence
categories are:
-------
- 6 -
o Known Positive
A convincing body of evidence exists that an agent causes an adverse
effect on the male reproductive system in humans.
o Probable Positive
A convincing body of evidence exists that an agent causes an adverse
effect on the male reproductive system in nonhuman mammals.
o Possible Positive, divided into categories which cause downgrading of the
weight of evidence, either
A. Evidence frcm human or other mammalian studies show statistically
significant adverse effects, but the quality of the studies is
questionable;
B. Studies with acceptable quality produce inconsistent and conflicting
results such that the possibility of adverse effects cannot be
discounted; or
C. Other data exist from which biologically meaningful adverse effects
are plausibly indicated.
o Known Negative
A convincing body of evidence exists that an agent does not cause an
adverse effect on the male reproductive system in humans.
o Probable Negative
A convincing body of evidence exists that an agent does not cause an
adverse effect on the male reproductive system in nonhuman mammals.
o Possible Negative
Studies with acceptable quality produce no adverse effects, but important
aspects of the male reproductive system have not been evaluated.
o No Data or Inadequate Data, subdivided into classes
A., No data are available;
B.- Negative data are available from studies for which the confidence in
quality is questionable; or
C. Results are available for which the predictive value of the test
system or end point has not been established.
-------
- 7 -
As with the female reproductive risk guidelines, the Dose-Response Assessment step
uses the Agency's current RfD approach, the Exposure Assessment step uses the
exposure guidelines, and the Risk Characterization step should be a discussion of
the estimation of the risk which also includes assumptions, scientific judgments,
and an estimation of uncertainties.
There are three guidelines that may be amended, or may have major additions:
developmental toxicity, exposure measurements, and carcinogenicity. Proposed
amendments to the developmental toxicity guidelines are undergoing pre-proposal
reviews. The current draft contains a weight-of-evidence categorization,
refinements to the RfD discussion, expanded discussions of the relationship
between maternal and developmental toxicity and of dose-response modeling
techniques, reformatting of sections on human studies and risk characterization as
well as updates to many of the other sections.
The draft Guidelines for Exposure-Related Measurements are at a similar stage
of development—undergoing pre-proposal review. These new guidelines are intended
as a companion and supplement to the Guidelines for Estimating Exposures. Those
earlier guidelines present the risk assessor with a format or procedural framework
for estimating the degree of human contact with a chemical of concern; they
recognize the importance of measured data, but recognize that there will be data
gaps which can be addressed by use of validated mathematical models. Comments
received on the earlier guidelines, especially comments from the SAB, suggested a
supplement dealing in more detail with how to make and use exposure assessments.
The measurement guidelines are, therefore, intended to assist those who must
recommend, conduct, or evaluate an exposure assessment. The draft guidelines
contain three major sections:
o sources of measurement data for direct measurement, reconstructive
approaches (body burden, metabolites, biomarkers) and predictive
approaches to exposure assessment
o making exposure measurements—including the role of the exposure
assessor, sampling plans, uncertainty analysis, quality control, quality
assurance and model selection
o use of measurements in exposure assessments, including evaluation of
uncertainty in'use of measurements; quality assurance and the role of
limit of detection values; and the relevance of the various forms of
measurement data, including the relationship between measurements and
modeling and the combination of measurement data sets from various
sources
In contrast to the developmental toxicity and exposure measurement projects,
the process for amending the carcinogenicity guidelines is just beginning.
A recent Federal Register Notice publicized EPA's intent to review the
carcinogenicity guidelines and requested that relevant information be submitted by
October 11, 1988 (U.S. EPA, 1988d). That notice also states EPA's plans to hold a
workshop in early 1989 (date not yet set) and to propose amendments, if any are
-------
- 8 -
appropriate, by the fall of 1989. The notice sets out several issues that have
been designated for consideration, in addition to issues that will be raised as a
result of the Federal Register solicitation for information. These designated
issues include:
o Classification Scheme
consideration of options for the weight-of-evidence scheme.
Experience with the current scheme indicates some need for change,
for instance, either adding more categories (as in European and
international chemical industry schemes) or limiting them
clarification of terms like "sufficient," "limited," and
"inadequate" both in terms of changes in the International Agency
for Research on Cancer's (IARC) definitions and in terms of our own
experience
other classification issues
o Decision Logic for Quantitative Risk Estimation
developing guidance on when quantification is appropriate for
category C chemicals
considering additional approaches for characterizing the risk
+ newer or updated methods for calculating or caning close to the
"best" estimates of risk to determine whether any are
appropriate for inclusion in the guidelines
+ fully stating the qualifying considerations that affect the
accuracy of risk estimates like the "plausible upper bound"
+ providing guidance on selection of other extrapolation models,
especially those that take into account biological mechanisms
and pharmacokinetics
expanding guidance on pharmacokinetics and interspecies scaling
factors
o Other Issues which would not alter basic concepts in the guidelines
updating them for current knowledge of mechanisms of carcinogenesis
~ such as site and contact of hormonal carcinogenesis; the role of
cellular peroxide formation; the use of promotion studies; data on
genotoxicity; information on onoogenes; and considerations of
structure-activity relationships, metabolism, and pharmacokinetics
additional guidance on combination of benign and malignant tumors,
where EPA appears to differ in approach from IARC and the National
Toxicology Program
-------
- 9 -
additional guidance on risk characterization, e.g., types of
analyses to be conducted, articulating risk findings such as use of
sensitivity analyses, expressing variability in risks, and
quantitation when the weight of evidence is low
incorporation of Risk Assessment Forum reports
Another area of guidelines interest is dose-response estimation for threshold
toxicants. This was an area that was of significant interest from the start of
the process in 1983-1984. However, guidelines in this area have not been
developed because of the difficulty we have had in reaching consensus for such a
broad area. This covers many end points and many different target organs that
could be considered for any one chemical. In the absence of consensus procedures,
each program office at the EFA has historically approached the problem in
different ways. Examples include evaluating a specific adverse health effect
rather than determining the critical health effect (the adverse health effect
occurring at the lowest dose), or assessing risk for less than lifetime exposure
rather than determining a lifetime chronic acceptable daily intake (ADI) or
reference dose (RfD). In addition, program offices have used different approaches
for dealing with uncertainty. Some have estimated a lifetime chronic RfD based on
uncertainty factors tied to the available "information, and then established
criteria based on that RfD. Some have calculated a margin of exposure (formerly
margin of safety) between the highest no-observed-adverse-effect-level (NDML) of
the critical effect and the estimated exposure, and then evaluated that margin
specifically in terms of the chemical of interest and its expected exposure
pattern. Some offices have estimated an appropriate degree of protection on a
case-by-case basis, using their best technical and scientific judgment; this is
analagous to the process of developing National Ambient Air Quality Standards.
Finally, some programs have developed their own quantitative techniques for
extrapolating or interpolating across data gaps; few of these have yet gained
general acceptance within the Agency.' The guidelines development effort was
suspended while an Agency-wide effort was begun to develop consensus RfDs and
enter them into the new Integrated Risk Information System (IRIS; U.S. EPA,
1988e). In addition to the specific chemical files, IRES contains a discussion of
the approach used for developing these consensus RfDs. IRIS is currently
available thru EPA's E-mail, the Public Health Foundation Network, and shortly on
TOXNET. It is also updated quarterly for the National Technical Information
Service and purchased from them by private data sources. An Agency work group is
continuing to consider the development of risk assessment guidelines generically
for non-cancer health effects such guidelines.
The Agency also has a continuing interest in developing effect-specific
guidelines for some non-cancer health effects. The first effect-specific
guidelines for threshold effects are the Guidelines for the Health Assessment of
Suspect Developmental Toxicants published in 1986 and the Proposed Guidelines for
Assessing Female Reproductive Risk and for Assessing Male Reproductive Risk,
discussed previously. The next effort is neurotoxicity. A work group has been
developing such guidelines. Beyond neurotoxicity, future development of
guidelines for immunotoxicity is being considered. Also under consideration for
future work are guidelines for more generic issues like ecological risk and
pharmacokinetics. These so called future projects are indefinite only in the
-------
- 10 -
sense of there being no planned date for completion of guidelines. Projects are,
in fact, underway in all three areas to develop risk assessment tools and
techniques that could become the basis for guidelines in what might be called the
third round.
When EPA initiated its program of guidelines development almost five years
ago with the first five guidelines, the Agency expressed a continued intent to
update and revise them, and to add to them as appropriate. Our plate is full for
the next few years, and our interest continues beyond this second round. Our
intent is to continue to amend or add to the guidelines, as the sophistication of
risk assessment increases, as more risJc assessments are performed, and as long as
there is a continued need for the assurance of quality and consistency in the
Agency's scientific evaluations.
-------
REFERENCES
National Research Council. (1983) Risk assessment in the federal government:
' managing the process. National Academy Press, Washington, DC.
Preuss, P.W. and Ehrlich, A.M. (1987) The Environmental Protection Agency's risk
assessment guidelines. J. Air Poll. Control Assoc. 37:784-791
U.S: Environmental Protection Agency. (1986a) Guidelines for carcinogen risk
assessment. Federal Register 51:33992-34003.
U.S. Environmental Protection Agency. (1986b). Guidelines for mutagenicity risk
assessment. Federal Register 51:34006-34012.
U.S. Environmental Protection Agency. (1986c). Guidelines for the health risk
assessment of chemical mixtures. Federal Register 51:34014-34025.
U.S. Environmental Protection Agency. (1986d). Guidelines for the health
assessment of suspect developmental toxicants. Federal Register 51:34028-34040.
U.S. Environmental Protection Agency. (1986e). Guidelines for estimating
exposures. Federal Register 51:34042-34054.
U.S. Environmental Protection Agency. (1987, August). Hie risk assessment
guidelines of 1986. Office of Health and Environmental Assessment, Washington,
D.C. EPA/600/8-87/045.
U.S. Environmental Protection Agency.. (I988a, June 30) Proposed guidelines for
assessing female reproductive risk. Federal Register 53:24834-24847.
U.S. Environmental Protection Agency. (1988b, June 30) Proposed guidelines for
assessing male reproductive risk. Federal Register 53:24850-24869.
U.S. Environmental Protection Agency. (1988c, August 26) Proposed guidelines for
assessing female and male reproductive risk: extension of public cament period.
Federal Register 53:32658.
U.S. Environmental Protection Agency. (1988d, August 30) Intent to review
. guidelines for carcinogen risk assessment. Federal Register 53:32656-32658.
U.S. Environmental Protection Agency. (1988e, June 2) Integrated Risk
Information System (IRIS); health risk assessment; guidelines, etc. Federal
Register 53:20162-20164«
-------
Figure 1
TOXICS INTEGRATION TASK FORCE
RISK ASSESSMENT SUBCOMMITTEE
RECOMMENDATIONS
RISK ASSESSMENT GUIDELINES
COORDINATE RISK ASSESSMENT PROCESS
-------
Figure 2a
RISK ASSESSMENT
Dose-Response
Assessment
Risk
Characterization
Hazard
Identification
Exposure
Assessment
-------
figure 2b
Risk
Characterization
-------
Figure 2c
Think
Organize
Conduct
Present
Data
Risk
Characterization
-------
figure 2d
ISK
ESSMENT
»„.*
MANAGEMENT
Social
Legal
Economic
Political
f
Risk
Characterization
Regulatory
Decision
-------
Figure 3
RISK ASSESSMENT GUIDELINES
USE AND INTENT
CONSISTENCY
TECHNICAL QUALITY
CLARIFY SCIENTIFIC ASSUMPTIONS
FLEXIBILITY
PROVIDE PUBLIC WITH
EPA "KOAD NAP"
-------
Figure 4
RISK ASSESSMENT GUIDELINES
DEVELOPMENT/REVIEW PROCEDURE
INTRA-AGENCY WORK GROUPS
INVITED EXPERT REVIEW
RISK ASSESSMENT FORUM REVIEW
RISK ASSESSMENT COUNCIL REVIEW
PROPOSAL FOR PUBLIC COMMENT
SAB REVIEW
FINAL AGENCY REVIEW
OMB REVIEW
FINAL PUBLICATION
-------
_ Figure 5
RISK ASSESSMENT GUIDELINES
ISSUED 1986
CARCINOGENICITY
MUTAGENICITY
DEVELOPMENTAL TOXICITY
ESTIMATING EXPOSURES
CHEMICAL MIXTURES
-------
__ _ ..Figure 6
RISK ASSESSMENT GUIDELINES
CURRENT PROJECTS
FEMALE REPRODUCTIVE RISK
MALE REPRODUCTIVE RISK
EXPOSURE MEASUREMENT
DEVELOPMENTAL TOXICITY (AMENDMENTS)
NEUROTOXICITY
NON-CANCER HEALTH EFFECTS
CARCINOGENICITY (AMENDMENTS)
AS OF SEPTEMBER, 1988
-------
. _ Figure 7
FEMALE REPRODUCTIVE RISK
MALE REPRODUCTIVE RISK
CHRONOLOGY
PROPOSED JUNE 30, 1988
SCIENCE ADVISORY BOARD REVIEW JULY 14, 1988
COMMENT PERIOD ENDS SEPTEMBER 30, 1988
-------
_ _. - ..Figure 8
PROPOSED REPRODUCTIVE RISK GUIDELINES
FORMAT
HAZARD IDENTIFICATION
O LABORATORY STUDIES
O HUMAN STUDIES
o PHARMACOKINETICS
O MOLECULAR STRUCTURE ANALOGS
O WEIGHT OF EVIDENCE
DOSE RESPONSE ASSESSMENT
O REFERENCE DOSE
EXPOSURE ASSESSMENT
RISK CHARACTERIZATION
-------
Figure 9
MALE REPRODUCTIVE RISK GUIDELINES
WEIGHT-OF-EVIDENCE CATEGORIES
KNOWN POSITIVE
PROBABLE POSITIVE
POSSIBLE POSITIVE
A. STUDY QUALITY UNCERTAINTY
B. CONFLICTING RESULTS
C. OTHER DATA
KNOWN NEGATIVE
PROBABLE NEGATIVE
POSSIBLE NEGATIVE
NO DATA/INADEQUATE DATA
A. NO DATA AVAILABLE
B. NEGATIVE, BUT STUDY QUALITY UNCERTAIN
C. PREDICTIVE VALUE UNCERTAIN
-------
Figure 10
RISK ASSESSMENT GUIDELINES
AMENDMENTS/ADDITIONS
DEVELOPMENTAL TOXICITY
EXPOSURE-RELATED MEASUREMENTS
CARCINOGENICITY
AS OF SEPTEMBER, 1988
-------
- -- ' "Figure 11
CARCINOGENIC ITY GUIDELINES AMENDMENTS
SCHEDULE
•
INFORMATION SOLICITATION OCTOBER 11, 1988
WORKSHOP EARLY, 1989
PROPOSED GUIDELINES FALL, 1989
AS OF SEPTEMBER, 1988
-------
- — - --Figure 12
CARCINOGENICITY GUIDELINES ISSUES
) CLASSIFICATION SCHEME
- WEIGHT-OF-EVIDENCE
- DEFINITIONS
- OTHER CHANGES
> QUANTITATIVE RISK ESTIMATION
- CATEGORY C
- MLE V. UCL
- SCALING FACTORS
• OTHER ISSUES
- MECHANISMS"OF CARCINOGENESIS
- BENIGN AND MALIGNANT TUMORS
- RISK CHARACTERIZATION
- FORUM REPORTS
-------
FIGURE IJ
NON-CANCER HEALTH EFFECTS
(SYSTEMIC TOXICANTS)
DIFFERENT APPROACHES
I.
END POINT SELECTION
EXPOSURE PERIOD
DOSE-RESPONSE CALCULATION
UNCERTAINTY ADJUSTMENT
HANDLING DATA GAPS
-------
figure 14
FUTURE GUIDELINES
OTHER SPECIFIC HEALTH EFFECTS
- NEUROTOXICITY (UNDERWAY)
- IMMUNOTOXICITY
ECOLOGICAL RISK
PHARWACOKINETICS
OF SEPTEMBER, 1988
------- |