ELEMENTS OF
RISK ASSESSMENT
Dr. Bernard Goldstein
       Environmental
       Protection Agency
Risk Assessment Conference
March 18. 1985

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WHY A CONFERENCE?
Inform groups affected by EPA
actions about a critical part of its
decision-making process:
risk assessment
•  Define elements
$  Describe uses and imitations
ft  Demonstrate performance by EPA
                   COMMENTS

(Introduction by Dr.  Goldstein)

Why a conference?

    •  The Agency vents to tell group* concerned with
      BPA action* about the use of riak assessment
      in regulatory  deciaion Baking.
Why?
      •iak assessment ia increaaingly  being uaed  in
      the regulatory process.

      People need to develop an underatanding of
      riak aasesaaent to underatand EPA decisions.

      Failure to cosvunicate adequately in the past
      has led to pr obi eats in public understanding of
      EPA'a deciaiona (e.g.. Love Canal, EDB).

      Finally, I would like to eaiphaaice we are here
      to infona you, not indoctrinate.

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WHAT IS RISK?
The likelihood of injury, disease,
or death

WHAT IS
ENVIRONMENTAL RISK?
The likelihood of injury, disease,
or death reselling from human
exposure to a potential
environmental! hazard
             CGNMBNT3

There are many types of risk.  However, at
thia conference we are concerned with chemical
expoaurea—particularly, riaka that people
confront on a day-to-day baaia.

Riak aaaeaament incorporatea both qualitative
and quantitative aaaeaaaientai  the qualitative
aaaeaament of whether the riak will occur and
the quantitative aaaeaaaent of the magnitude
of the riak.
                                 •
The need for riak aaaeaament ia uaually
prompted by the reaulta of reaearch or human
experience which auggeata that adverae effect*
•ay be cauaed by the expoaure.

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COMPARATIVE RISKS
OF DEATH
                  Number of    Lifetime
                 Deaths/Year   Risks
• Motor vehicle    46,000
  accidents
• Home
  accidents
• Lung cancer
  deaths in
  smokers
25,000

80,000
              1/65
1/130
             COMMENTS

All  human activities carry aoae degree of
risk.  There are some activities for vhich the
actual riak can be readily Measured, for exam-
ple, awtor vehicle accidents.  These are often
activities for which the riak is very high or
for  which the number of people exposed to the
risk is very large (e.g., Motor vehicle acci-
dents), and for which the outcome can be
readily attributed to the exposure.

With most chronic chemical exposures, however,
assessment of the risks is more complex be-
cause the association between cause and effect
ia difficult to identify, particularly if the
risk ia low or the nuaber of people exposed is

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               COMMENTS

Research include* studies of the toxicology of
the substance in question, caae reports of
effects in husans following exposure,  huaan
epidemiologic studies of populations exposed
to the substance, and estimation of human
exposure levels.

Such data, however, do not lend themselves
directly to regulatory decision Making or what
ia known within parts of EPA as risk Manage-
ment,  for example, research may indicate that
a substance.causes liver damage in rats at a
certain high doae level.  Further analysis is
necessary to make a decision about an allow-
able level of expoaure to the aubatance to
protect the public health.  A major component
of this step is known as risk assessment.
Part of the risk assessment process involves
making inferencea from often limited scien-
tific data on the basis of what we currently
know about the underlying biological
processes.

It should be noted that risk assessment is
only one element of the ultimate riak manage-
ment process.  In addition to public health
considerations, economic, political, and
social consequences are generally considered.

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WHAT ARE THE
COMPONENTS OF
RISK ASSESSMENT?
•  Hazard Identification
•  Dose-Response Evaluation
•  Human Exposure Evaluation
•  Risk Characterization
                   COMMENTS

   The EPA'* Method i* based on the process de-
scribed by the National Academy of Science*.

   •  HsKard identification;  The determination of
      whether a particular chemical ia causally
      linked to particular health effecta.

   •  Dose-response evaluation;  The determination
      of the relation between the magnitude of expo-
      sure and the probability of occurrence of the
      health effecta.

   •  Human exposure evaluation;  The determination
      of the extent of human exposure before or
      after application of regulatory controls.

   •  Bisk characteritation;  The description of  the
      nature and often the magnitude of human risk,
      including attendant uncertainty.

    Before describing the individual steps of risk
assessment, I would like to discuss the biological
basis  for performing this process  ...  (next three
slides)

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RISK ASSESSMENT

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STRUCTURE OF DNA
Normal TraraafclkM Abnormal Transcr^tfon
DMA Prorate DNA Protafa
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)-* («*!>!) -»Qly
A
T
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--• 	 r\ . t «i
etna v»^i HI
A
i T
T Asparagina T
A f
1 A
•
• • •
• • •
• • •
Arginina
1
iml-»QlwekiA
VM » ^r\jiy **• 10
1
Asparagina
1
•
•
•
               COMMENTS

DMA contain* the coded information that regu-
late* the growth of all organisms.

Damage to DNA or alteration in the eequence of
bases may affect how growth ia regulated.  One
posaible outcome of thia ia cancer.

It ia theoretically poaaible that a a ingle
molecule of a carcinogen could produce an
alteration in the DNA aequence at a critical
•ite, which could aubcequently reault in can-
cer.  Mathematical modela have been developed
to take thia poaaibility into consideration.

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^Threshold
Non-Threshold
No Elf act   Organ Damage
                  COMMENTS

•  Non-Threshold:   For effect* that involve
   •Iteration of genetic Material (including the
   initiation of cancer), a very amall exposure
   to a chemical may be aufficient to produce an
   alteration in one cell.  Thia altered cell may
   in turn multiply to font a tumor.  Thus for
   effeeta auch aa cancer it ia commonly believed
   that there ia no threshold or no absolutely
   aafe level of exposure.

•  Threshold:  For most other biological effects
   it ia generally believed that a certain mini-
   mum exposure ia necesssry before any altera-
   tion in function of an organ or organ aystea
   is produced.  For example, a certain minium
   number of eella must  be damaged before the
   compensatory ability of the organ becomes
   overwhelmed, resulting  in a measurable effect.

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HOW DO WE DEFINE
WHETHER A CHEMICAL
IS A CARCINOGEN?
                COMMENTS

•  Determining whether a  substance is * carcino-
   gen is usually not • YES-NO decision.  This
   detersiinstion is based on the total weight of
   evidence.

•  Rather, substances csn be placed along a con-
   tinuum fro* definitely not carcinogenic to
   definitely carcinogenic in humane.

•  Por example, sodium chloride (i.e., salt) ie i
   substance about which  we are aa confident ae
   science will allow that it is not a
   carcinogen.

•  Bensidine, on the other hand, ia known to
   cause csncer in humans and in the majority of
   animal species in which it haa been tested.

•  The great majority of  other substances fall
   somewhere between these extremes and the cut-
   off for classifying a  substance as carcino-
   genic is subject to debate.

(Here you can discuss:  'How much of a  tumor
increase is considered to represent a carcino-
genic response?M)

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HAZARD
•  Review and analyze toxicity data
•  Weigh the evidence that a
   substance causes various toxic
   effects
•  Evaluate whether toxic effects in
   one setting will occur in  other
   settings
             COMMENTS

Hazard identification includea assessing
whether the data meet currently accepted
atandarda of deaign,  conduct, pathologic
evaluation, and atatiatical analyaia.

Do the experimental result*, taken aa a whole,
aupport the concluaion of causality?

Under what conditiona of exposure, in what
speciea, have toxic effecta been obaerved?

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TOXICITY STUDIES
  Indicate specific organs or systems
  of the body that may be damaged
  by a substance
  Identify specific diseases that a
  substance may produce, such as
  cancer or birth defects
  Describe  conditions of exposure
  that may  result in these effects
             COMMENTS

But stance* may cause a * id.  range of toxic
effect*.  These- mmj ranee • ro» relatively
•icor effects, such as skin irritation,
through variou» foms of organ damage, to
potentially lethal effecta such as cancer.

Individual cheeicals cae cause various forais
of toxicity. For example, consuaption of
alc:ohol can cause central nervous system de-
pression, delirium tremena (DTs), liver
toxicity, and adverse effects on the develop-
ing fetus.

The purpose of toxicity  tests is to determine
what foms of toxic effects a chemical may
cause and under which conditions  (such aa
route of administration, dose, duration) they
may occur.

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SOURCES OF TOXICITY DATA
  Himum Studies
Case reports
EpktemfGlogfc studies
• Geographical
• Temporal
     Anbnal Shxfes
Qeneral toricfty studfes
• Actile
• Chronte
Spedabed loxldly studtes
• Teratology
               Test TubeStudjes

               • Mammalon
                 tXMMENTS

»  Ca*'* reports;   tocontrol'ed anecdotal report*
   on idverse effect* in individuals who have
   been exposed to the subsi an :e.

*  Epi'iemiologic *f.udiest   Con:rolled atudiea
   thai: compare the health «ta:us of a group of
   pernoaa who have been exposed to a substance
   with that of a comparable nonexpoaed group.
                                                                  atudiea;  In general  toxicity atudies,
                                     aniawla are exposed to varying doaea of a
                                     substance, by varying routes, and for varying
                                     duration*.  During and following exposure,
                                     anlaala are examined to detect varying acute
                                     or chronic (i.e., lifetime) effecta on a range
                                     of endpointa (e.g., survival, body weight,
                                     effect* on • peel fie organa and ays teas).

                                     Animal toxicity studies are conducted baaed •
                                     primarily upon the long-standing assumption
                                     that effect* in humans can be inferred from
                                     effect* in animals.  This an sumption haa been
                                     shorn to be generally correct.
                                                           —All  the chemical* that  have  been demon-
                                                             strated to be carcinogenic in human*, with
                                                             the  possible exception  of arsenic, are car-
                                                             cinogens in some—although not all—experi-
                                                             mental animal apeciea.

                                                           Some effecta (e.g., teratologic, mutagenic)
                                                           require special measurement techniques.

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DOSE-RESPONSE EVALUATION
   Performed to estimate the incidence
   of the adverse effect as a function
   of the magnitude of human exposure
   to a substance
    Response
              X
                ,:«l»:
                       Dose
               CCHMENT8

•  Dote- response evaluation it generally per-
   fom«d to awasurt the advcra • effect that ia
   likely to occur *t the loves expoaure level.

•  It generally involves two atcpa:

   1.  Extrapolation froai high to lov doae (in
      animals)

   2.  Extrapolation from aniaula to huaana

•  The firat atep generally involves the use of a
   •atheaatical aodel to infer riak at low doae
   levels.

•  The second atep adjusts for differences, such
   aa body aixe and life span, between experi-
   mental animals and hunana.

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DOSE-RESPONSE CURVE
                                ervable
                                 Range
                              Range of
                              Inference
                           Dose
                                            Rote:
              nOHMBNTS

Thi.e elide shots e hypothe icel  done-response
cut ve.

The aolid line indicates the shape of the
doie-response c ;irve  in the range of riak
levela that ear  be practici lly exanined in
experimental studies.

Explain statistical  liatitai ions  on the levels
of riak that e*... be  studied experimentally.

The dotted linea indicate plausible extensions
of the doae-reaponae curve to the low-dose
region in which humana are actually exposed.
Bach of the dotted lines repreaenta a plaus-
ible Mathematical model.
                                                   The Mathematical aodel choaen to infer risk at
                                                   low-dose levela should be coapatible with our
                                                   underatanding of the awchania* by which the
                                                   cheaical exerta ita toxic effect (threshold
                                                   veraua non-threahold).

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      FORMS OF
HUMAN EXPOSURE
      Inhalation
      digestion
      Skin Contact
               COMMENTS


<•  Expiaure May oc ur by v« -it ua routes.


o  A aubatance «ay be:


   —•Ingeated in f tad or wa :ei


   —Inhaled through the ai :


   —-Abeorbed through the a*ie


•  A peraon «ay be expoaed to a particular
   aubatance by any or all of theae routea,

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HUMAN EXPOSURE
EVALUATION	
• How may people be exposed?
• Through which routes?
• Who is exposed?
• What is the magnitude, duration,
  and timing of the exposure?
                COMMENTS

•  Piri't, we mutt determine in which Media the
   aubiitance may bn present (a r, water,  food,
   soil ).

•  MexC, we determine how pcop e may be exposed
   to  l:he awdia in which the  a tbstance ia present
   (inhalation, drinking, eating, akin contact).

a  lie  then identify population groups who maj be
   exposed, including their sixes and character-
   istics.

a  Next, we determine, by actual Measurement or
   by  environmental fate modeling, the concentra-
   tion of the substance in these media and the
   amount of human intake through expoaure to
   theae media.

•  Obviously, there are many uncertaintiea asso-
   ciated with each of these atepa.  A common
   source of this uncertainty sterna from  the
   distinction between modeling data and  actual
   monitoring data.

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Identification Data
 Dose*Responsf»
 Evaluation^ Data
 Human Exposure
 Evaluation Data
      Risk
Characterization
                     COMMENTS

title characterisation:

    *  Integrates the data collect«d  in  the  firat
       thr.se  atepa to character: ««  the potential riak
       to
                            o  Deacribea the  atatiatical and biological un-
                               certainties in eatiMting the extent of health
                               effecta.

                            In this final step,  riak mmj be characterised in
                         several vaya:

                            •  Developswnt of an explicit numerical estimate
                               of the riak for each population group.

                            •  Eatiauition of  the Margin of safety for each
                               population group  (i.e., NOEL * estimated
                               dose).

                            •  Qualitative deacription of riaka for each
                               population group.

                            •  BOSM combination  of  these three approachea and
                               SOM description  of  their awrits.

                         Mote:  For all four approachea, it is essential that
                               the atatiatical and  biological uncertaintlea
                               be deacrlbed.

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RISK ASSESSMENT ISSUES
                Use of animal data
Hazard
Identification
                Negative epidemic-
                logical studies
                                                           ooFMnrrs

                                             Here are BOM iaport^at iaauet • i«ociate4 with
                                          each (tap of the riak ••r-easaent  | ro :e«* that I would
                                          like to reeajihasice . . ,-

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ADVANTAGES AND
UNCERTAINTIES
OF ANIMAL
DATA
           or DIBITS

Humans ar« not jutt big r« :•.  They differ in
• Ice, life span, laetabolian, physiology, and
anatoiy. That, ujing animil data involve*
uncertainties related to t'ieia difference*.

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RIS!: ASSESSMENT ISSUES
Hazat d         Use of animal data
Identi ication
               Negative epidemio-
               logicaS studies

Dose-Response  Extrapolating from high
Evaluation      dose to low dose

               Extrapolating from
               animals to humans

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HIGI [-TO-LOW DOSE PROBLEM
  R
  e
  s
  P
  o
  n
  s
  e
     able
   Range
Range of
Inference
                              Dose
             COMMENTS


Cener.illy,  the avi liable d< tm involve high

«itpoatire levels it aniaiala  (or huauma) and
aeaoc ated  high r <*ka.


He mint infer how riek altsra with changea in

espoanre levela.  Varioua todtla have been

developed baaed or current  th :ory from which

to drnw theae inf« rencea.

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RISK ASSESSMENT ISSUES
Hazard
Identification
Dose-Response
Evaluation
Use of animal data

Negative epktemWogteal studfes

Eitranoiating from Hgh
dose to low dose

Extranotetmg from
anfcnate to humans
Human Eiposure   Modelng vs. ambienl monitoring
EvaluaUon
vs. biological monttoriny

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               COMMENTS

Bnpoaurs evaluation can be porf^raed baaed
on actual environmental aoni :oilog data or the
application of aathaMtical nxp>aure aodela.
Both Method* involve uncerta.ntr*

Monitoring data often involvua i liaited
nuaber <>f •••pies, on a ••all portion of an
axpoaed population, and liaicatlona in
aenaiti'rity and accuracy of i«t*oda.

Modeling data mtj be aubject to queatioo due
to uncertainty in the nae of •atheaatical
•odela to predict actual environmental
levels.

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RISK ASSESSMENT ISSUES
Hazard
IdentiUcaUon
Do*e -Response
Evaluation
Humcn Exposure
Evaluation

Risk
Characterization
Use of anhnal data

Negative epMeiiJolopjteai studies

Extrapolating from Mg0i
dose lo low dose

Extr apotattig from
animals to humans

Moddhg vs. ambient monftonng
vs. biological monitoring

Ouaitattveor
quantitative

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RISK CHARACTERIZATION
32? per 1,000,000 exposed people wl dto
from Ifetkne expos*** to Chemical A.
              COMMENTS

Thia slide  demonstrates ths tange of waya in
whicti riak  of cheaical expoaire m»j be
characterised.

In tie top  example, riak ia thwracterised in
quantitative term* with no firther
explanation.

In the aecond example, the riak aaaeaaor
determined  that the chemical waa carcinogenic
in two laboratory animal apeciea and, through
the uae of  lov-doae extrapolation model* and
human expoaure eatimatea, predicted a range of
poaaible riaka to an expoaed population.

In the final example, riak in laboratory ani-
mala ia characterised in qualitative terms
only; no prediction of the riaka to humana ia
made.

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R! >K CHARACTERIZATION
32V par 1,000,000 exposed people vrii dfe
fror i If eftne exposure to Ctiemleal A.

Chemnical A It cardnogetito h rate and mice.
Appication of low-dose eitrapototton
moc^eb and human eiposura esttmatea
       that the range off rtaka hi humans
ts 1UO-1tOOO deaths per 1JOOO.OOO persona
exposed.

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RISK CHARACTERIZATION
927 per IjOOOjOOO exposed people wl db
from if etime exposure to Chemical A.

Chemical A b carcmogento hi rate and mice.
Apfication ol low-dose extrapolation
models and human exposure estimates
suggests thai the range of risks at humans
b 100-1,000 deaths per 1JQOO.OOO parsons
exposed.

Chemical A b cardnogenta b rats and nice
and II b prudent pubac heaiUi polcy to
assume It b abo carcinogenic In humans.

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Range of expert judgment

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Range off expert judgment
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