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

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                                    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.

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                    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

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                                      - 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.

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                                      - 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

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                                      - 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

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               +    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:

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                                 - 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.

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                                      - 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

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                                     - 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

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                                      - 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

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                                      -  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.

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                                    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«

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          Figure 1










TOXICS INTEGRATION TASK FORCE




RISK  ASSESSMENT SUBCOMMITTEE








       RECOMMENDATIONS






  RISK ASSESSMENT GUIDELINES






  COORDINATE RISK ASSESSMENT PROCESS

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           Figure 2a
RISK ASSESSMENT
         Dose-Response
          Assessment
                   Risk
               Characterization
  Hazard
Identification
           Exposure
          Assessment

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figure 2b
                        Risk
                 Characterization

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                         Figure 2c
    Think
                 Organize
Conduct
                                               Present
Data
                                              Risk
                                        Characterization

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                     figure 2d
 ISK
 ESSMENT
»„.*
MANAGEMENT
        Social
                  Legal
          Economic
                                      Political
      f
     Risk
Characterization
                  Regulatory
                   Decision

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         Figure 3
RISK ASSESSMENT GUIDELINES

      USE AND INTENT



        CONSISTENCY


        TECHNICAL QUALITY


        CLARIFY  SCIENTIFIC ASSUMPTIONS


        FLEXIBILITY
        PROVIDE  PUBLIC  WITH
          EPA  "KOAD NAP"

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              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

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   _	Figure 5








RISK ASSESSMENT GUIDELINES



        ISSUED  1986






CARCINOGENICITY






MUTAGENICITY






DEVELOPMENTAL  TOXICITY






ESTIMATING  EXPOSURES






CHEMICAL MIXTURES

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         __ _  ..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

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      .  _	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

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       _  _. -  ..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

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              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

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             Figure 10






     RISK ASSESSMENT GUIDELINES




        AMENDMENTS/ADDITIONS






DEVELOPMENTAL TOXICITY






EXPOSURE-RELATED MEASUREMENTS






CARCINOGENICITY
                              AS OF  SEPTEMBER,  1988

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           -  -- '  "Figure 11


          CARCINOGENIC ITY GUIDELINES AMENDMENTS

                   SCHEDULE
                                                 •
INFORMATION SOLICITATION           OCTOBER 11,  1988

WORKSHOP                           EARLY, 1989

PROPOSED GUIDELINES                FALL,  1989


                                   AS  OF  SEPTEMBER,  1988

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      -  — -  --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

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         FIGURE  IJ


NON-CANCER HEALTH EFFECTS

  (SYSTEMIC TOXICANTS)


 DIFFERENT APPROACHES
                   I.

  END POINT SELECTION

  EXPOSURE  PERIOD

 DOSE-RESPONSE CALCULATION

 UNCERTAINTY ADJUSTMENT

 HANDLING DATA GAPS

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               figure 14
           FUTURE GUIDELINES






 OTHER SPECIFIC HEALTH EFFECTS




 - NEUROTOXICITY (UNDERWAY)



 - IMMUNOTOXICITY
ECOLOGICAL RISK







PHARWACOKINETICS
                                 OF SEPTEMBER, 1988

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