UNITED STATES ENVIRONMENTAL PROTECT I O^A^xg-N'Qy'J.S Envronrnenta!
WASHINGTON, o.c. 20460 Projection Agency Library iviD-108
19, 1985
Hon.L~-M.ita-. JUNS 81988
Administrator „_. ,
U. S. Erwiroonental Protection 1200SixthAvenue/^iie^WA98101
Agency THE ADMINISTRATOR
401 M Street S. W.
Washington, D.C. 20460
Dear Mr. Thomas:
The Science Advisory Board has completed its preliminary scientific
review, as requested, of the^EPA Risk Assessment Guidelines for Carcino-
genicity, Mutagenicity, Chemical Mixtures, Developmental Effects and
Exposure Assessment./ To carry out its review the Board's Executive
Committee formed five Risk Assessment Guidelines' Review Groups consisting
of scientists with expertise in the subject matter of each guideline.
These groups met in public session on March 4 for a preliminary planning
meeting and on April 22-23 to discuss and evaluate a number of technical
issues with EPA staff as well as members of the_public. The Executive
Committee prescheduled its meeting for April 25-26 to expedite its evalu-
ation of the Review Groups' draft reports and to enable you to receive
the final SAB reports in a timely fashion. Enclosed are preliminary
reports on each of the five guidelines. As agreed to by EPA staff, the
chairs of each SAB Review Group will have the opportunity to see revisions
to the guidelines to determine which of the SAB suggested changes were
incorporated. If needed, the chairs may distribute the revised guidelines
to all members of the Peviev Group. Following this second review of the
revised guidelines, the chairmen will expeditiously prepare final reports.
The Risk Assessment Guidelines' Review Groups addressed two major
issues in their respective reviews. These included the adequacy of the
scientific rationale that identifies the need for guidelines and articu-
lates the conceptual framework behind their development, and the adequacy
of the Agency staff's interpretation of a number of technical issues
associated with each guideline. The major SAB conclusions and recommend-
ations for each guideline can be summarized as follows:
• The Carcinogenicity Guidelines Review Group advises that the
proposed, updated guidelines for cancer are needed. Since the
publication of the 1976 Interim Guidelines for Carcinogenicity,
considerable change has occurred in both the underlying scientific
data base and in the development of risk assessment methodologies.
The proposed guidelines are reasonably complete in their current
form. Two additional issues that need to be addressed include:
1) transplacenta!, multi-generational or total lifetime animal
bioassays, and 2) sensitivity analysis of the quantitative esti-
mate of potency. Regarding the Agency's interpretation of the
scientific issues, EPA's proposed guidelines are generally
consistent with the recently published Office of Science and
Technology Policy principles for chemical carcinogens, and they
address the important issues raised in the public conment
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Contincent en c~e adc~tion of minor revisions outlined in the
techni~al repo~ ~re~ared by b~e Revi0N Group, the prq?Osed guide-
lines are scientifically adequate for EPA staff to develop risk
assessments in support of ~~encf rlecision making.
. The ~utagenicit! Guidelines Review Group unanimously concurs b~at
the prcposed g~iGelines are based on an adequate scientific
rationale as determined by L~e existing state of k~cwledge in b~is
field. The guidelines represent a successful effort in articulatiO]
b~e background info~ation necessarj to develcp a risk estimation
approach for j ~dging t~e pJtential hlIrT"an mutagenici ty of a chenical.
Such an apPJac~ can t;e used to develop qualitative 'Neight-of-evidence
assessments and, in special cases, prcvides guidance to develop
quantitative risk assessments. The Review Group reccmmends that
an eight level rank ordering of studies be used in the weight-of-
evidence determination of qualitative risk. The Group also provides
the Agency with research rec~~ndations L~at, if pursued, would
supply EPA wiL~ needed and more precise tools for risk assessment.
. The Chenical ~1ixtures Revi2'N Group ccrnmends the EPi; work group for
developing a ve~! good draft of rational guidelines for health
risk assessnent in this veri complicated area of envircnmental
health. These guidelines were published later than the others and
EPA staff did not have time to incorporate changes based on public
camments. Agency staff agreed to submit a revised draft for the
panel's revieN prior to finalizing the guidelines. The principal
scientific recommendations wTIich the Review Group brings to your
attention include:
1. A need for revision of a summarj table which describes the
preferred a~proach to risk assessment eor chemical mixtures. The
table needs to be clarified and expanded to provide more options.
In particular, b~ere may be conditions in which the poor quality
of data am absence of relevant information could lead to a "non-
definable risk" cutCc:::ITe.
2. Developing ard incorporatirg a system to express t.ILe level
of confidence associated with various steps in the risk assessment
process. This might include a weight-of-evidence approach analagous
to the classification system for carcinogens developed 'by the Inter-
national Ajency for Research on Cancer and \'.,'ould require development
of a taxoncny of chemical mixtures. Sensitivity analysis is also
recommended to assess t.~e im.pact of various uncertainties on risk
estimates.
3. Because L~e scientific ~ckground of health effects of
chemical mixtures is w~ry broad and diverse, and at t.~e same time
full of critical ~aps, there is a need for a separate do~nt
which in effect '..,'ould b2 a technical supr:ort dOC1..Ir.1ent for the guide-
~ines. The s~udy o~ interactic;ms of ch6:ticals in biological systems
1S a canparC\~lve.ly lJnr"lature SCle!lCe. PrCX]ress in improving risk
assessment 1.,'111 c€ unusually cependent uPJn prooress in the science
of interactions. -
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o The Development~l Effects Rev:sH GrGup concludes that, in general,
the proposed guidelines are sc:~nLi=:cally adequate and C~u.Brsurate
with the present state or ~~e s~ience. Tr,e field of developmental
toxicology is, however, partic~:arly 'Ne~~ ~ith respect ~o quantita~ive
asseSSITent. The proposed guiCe:'ines could be improved In the sectIon
addressin] the relationships of :"1.aternal toxici ty in canparison
to toxicity of the fee us. The jasis for quantitati~e assessmenL also
needs elaboration.
o The Ex"f:Osure lIssessrcent Revie
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The Science Advisory Board recognizes the significance of the effort
to d:velcp Risk Assessrrent Guidelines aro applauds t..'1e Agency for takirg
this initiative. \~en finalized, ~~ey should provide L'1e basis for greater
consistency in the development and utilization of risk assessments by all
the program offices and should assist the Agency's senior managers in c~
municatirg complex scientific issues to ~~e public. The Board appreciates
the opportunity to provide its advice on the guidelines and will pr~vi~e
any additional reviEW that is requested. An A;ency respJnse to the Board's
advice is requested.
Sincerely,
\\~, \\l';
Norton Nelson, C~airman
Science Adviso~l Board
'; 'v \/'
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RETG?~
3Y ~E
S..;R C.~CI0:CG:::~~:::C=T'! C;";=:::LI:JES REVI£;'1 G~CUP
INTRODUCfIO:J
On lI,pril 22-23, 1985, the S':'.3 ::\:.s:<' Assessment C-uic:elines' ~e'l:-?N
Group for C3rci~cgenicity met in ~ujli~ session to review a re'lised craft
of the lI.;;ency r s prq:csed Guidelines :cr CarcinOJen Risk .-\ssessrent. SPA
propcsed the Guidelines in :bverrJ::E!:', 1984. Public cO"rr.rents were received,
and a revised craft t.:""'..at inCQQor3t~ G'1e A;ency I s res;;cnse to tl-,ese
canments waS '7'.ace available to tl1e ?evie.... Gra.m. The camnents 2-210....
refer to L'1is"revised text and nct to L~e :bv~r, 1984 draft coc~~nc.
The Review Group advises that ~ew guidelines for assessing cancer
risks are neerled. Since the publication of L'1e Incerim Guidelines
in 1976,1 boL'1 L'1e uncerlying scienci:ic info~ation and risk asses~ent
methods have ~anged considerably 31~~ough basic ~rinciples remain L~e s~.
Toe draft Guidelines are reascnably complete :n L~eir conceptual
framework and are sound in L~eir Dlerall iote~retation of the sciencific
issues. They are also generally ccrsistenc wi~~ L~e principles for
chemical carcinogens issued by L~e Office of Science and Technology
Poli~l (05TP),2 and address Lhe LT.portant issues raised by the public
comments. Contingent on the revisicns cutlined below, the draft Guidelines
should provide reasonable guidance for 2PA personnel to develop scientifi-
cally adequate based risk asses~nts in support or Agency decision ~aking.
The Review Group identifies L~re9 ~inds of !:'ecamnendations including:
(1) isslES :'iissirg fran the draft guidelines t..'1ac should te added; : 2)
generi'J.l advice that can be imp1e-rer1ted by t..'1e .:"c;ency ..vi t..ftout further
revie.v; ard (3) s~cific recanrrereacic~ for '....ordi:y; c-:.arges. :.1oSt: 'of
the Review Group's carments are in t:.e latter fo~ and represent a
carefully develqJed ccnsensus of L~e re'lie,.;ers. 8is s~cifici ty irxiicates
the extent to -...nich only minor c.'1anc;es are cd './i sed . 1he Revie'N Grcup
reqlEsts that ::P..; res;:ond to t.his r-e;;or: are, if !'":ec~sscry, to par:icularlv
indicate \mat ad'./ice was not used ~~~e~~er Nit~ a rationale for why it -
was not accepted.
1 U.5. Envirc~.er1t31 Prccection Age~=y, ~ealth ~isk and Eccnamic L~Dact
Assessments of Suspected Carcina;e:-:s: :::r1teri:"1 Procedures and Guid~lines
Federal Reaister 41: (May 25, 1976), 2:~02-21~OS.
2 Office of S-::ience are Technolcgy ?:;l:c~', C:cenic.'3l. Carcinogens
of the Science ard its ?<..ssociated ?ri.:-::::i91es - ?e2rtlary, 1985
Register 50: C.tarch l~, 1985), 10:3-:-1-1'1442.
- ..;. ?e'lie',oJ
ceceral
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l..
PROroSAL.S FS? .::V:;DITICNS ro TE:: GTID:::'=~;;::5
The Re'lie'N' GrCUD concludes t.'12: t'..;o ~di t.:.onal issues :lee::: to ::e
addressed in be cui6elines before '=-1.e'1 are :.:.:-:alized. L-.ese i:ccluc:e:
(1) transplacent9i, ~ulti-generatic:lal- or total li:eth~e ani~~ jicassays,
and (2) sensitivi t:j analysi3 of t.~e c:uantitat.:.':e esti.rnate of pLenc'!.
:::P-~ s~aff srDulci c:evelCD t.'1e (",ordin:: of t.1.e sec:ion on trarsDL:.cental,
~ulti-generational or total lifeti~~ jioassavs. The Revi~v Group has
;rcvided s:r;:ecific laryuage to t:e a::::::"2d :~r sers.:.':ivity analysis of c;:'...!an-
titative estimates. (See "ReCOT1Ire:1Cado;"s for Soecific I'lordiry C'1anges"
;. 29, below.) -
II.
GENERl\L CCM."1~'TS
The Revie'N' Grcup cdvises that t.1.e ~ency add a paragraph to the
introduction t.'1at describes t.'1e general differences between the current
'lers ion of the guidelines aOO the ::1:erb Gui=e~ ines of 1976. The numberirg
of t.'1e major sections also should t:e re'lissC, '..;i t11 the dcse-res~nse
section as ;;art II, the eXIXJsure sec:.ion as ;Be: III, and t.i)e risk char-
acterization section as part IV. r.-.e jistir.c:.ion eet'Neen GUalitati'le
ard qt.:anti tative assess:nent is impEci t t.~oughcut the dOCLTTTIent, but t.'1e
introduction should explicitly defi:-:e ~~ese te~.s. The references in the
prC90sed guidelines to the Office of Science and Yechnology Policy principles
need to define the relationship bet-Neen t.~e tONG doc~nts more explicitly,
that is, the OSTP docJment contains a general discussion of the scientific
basis for risk assessment whereas t.~e E?~ doc~.ent sets out practical
guidelines for carvjing aut risk asses~nt.
The panel me!'!'~rs proceeded t.'-:rcug::1 ::-.e reolis&d draft guidelines on ::n
issue by issue basis, first discuss::.; a:: iss~e :';1 .:etail and t~en testirg
G'1e revised draft 3gainst the disc~ssic;1. ~~e ~anel believes t.~at, in
general, the guideli~es adequately ~efi~e t.~e a3s~~ptions Dade in elaluating
G'1e scientific issues t..1tat are addr-essee. ~-::::Ne'.'er, the ~gency needs to
distinguish recan:':ErCations jased Cl scie"tEic e'licence fran those based
on science policy cc~ider3tions. =:: essence, ~?~'s recomnendations
represent choices ~~~een competing scie"ti:i.:: ~ypotheses for which t.~e
available data do not 3lways permit a clear decision. The draft guidelines
explain this distinction 'dell in d:SC:lssirq t:-:e use of the "linearized
Multi-stage ["'(Jdel" to develcp plausijle u;Jper :::-cund estL,;"ates of potency.
'The Review Grcuo SU8cests a similiar a;J::::roaCl for cuestions such as
extrapolation ~t.~; routes of a~inistraticn or extrapolation bet.Neen
species (body 'Neight 'lersus surface 2rea). ~e l2tter topic should refer
to more recent info~ation and ~ke clear b'1at consideration 0: ~re
sensitive hLIITBn sub;:opulations for.-:-:s ':...':.e rationale for selecting the most
sensitive anL~al species for quant::ication ~ur;C5es. The reccmmendatio~s
for extr2p:Jlation ::et-..een routes 0: ~"'1inisT:raT::..on need to make t.'1e orocedure
80re explicit. .
The Revie'''' Grout:' concurs wi t.'1 ;:.'".e ,;;encj I s stated [)Cs i tiors on cancer
praroters. The te!:TC1 "prOT\Oter" is c;:er3.t.:.onallj defined, and current
t'1i02ssay procedures co not !=€rmi t t.;"_e des ignati:Jn of a Clooical as
exclusively a promoter or an initiator.
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The ;'..cencl's senior SOECI of:i.:::ials should have sufficient flexibili ty
-'..... .L.;..
to define various options in decidi.~g whether to regulate specific c~pcunds.
Although L~e guidelines rE8resent a lcaical inout to establishing a policy
response, G~ey should not del~~it L~e series of factors, bob~ scientific ~nd
non-scientific, considered in regul2.t.Ory decisionmakirg. Control of ex::csure,
discJssed in the guidelines, seems to b~e Review Group to constitute only one of
a I1LlI11ber of available mtions. In cases '...here data ',."ere incdequat9 to make a
regulatory decis ion, b~~ Agency cculd recanrrend further testir9 or expcsure
evaluation on a priority basis. (See ~ge 6 of the revised draft.)
In developing the section on ~~e elements of hazard identification
the Revie,." Group suggests ~,at b~e guidelines draw the risk assessor's
attention to a series of issues t..':at ',..,ill influence the interpretation of
cancer risk. These include:
(1) Strengt~ of L~e evidence
(2) Promotion or co-carcinogenesis
(3) Maximum tolerated dose
(4) Mouse liver tumocs
(5) Renign t~~rs
(6) Statistical considerations
(7) Historical controls
(8) Negative data
(9) Positive data
(10) Interractions
(11) Variability in h~n response
Regarding the issue of less t.~an lifetime exposure, the Review Grout)
reccmrrends that the Agency iTT'prOtle on the rnethoris used in the guidelines
to develcp ranges of estimates. ~'hen usirx; the multi-stege f'1'1odel, reference
to the method of Crump and Howe will be useful. More generally, the
method of Gaylor am Kodell is suggested. The cocument should describe
alternative methods to deal ',..,it.h less than lifetime exposure.
In the description of b~e weig~t-of-the-evidence for epidemiological
data, biological plausibility and t~?Jral sequence should be mentioned as
factors to be considered in the e'Jaluation. Throughout the document the
term "v.eight-of-Ll1e-evidence" shoule: be used consistently, and reference
to apparent synonyms that may confuse, such as "degree-of-evidence" or
simply "evidence," should be deleted. The Review Group concurs with the
overall weight-of-the evidence categories developed by L~e Agency, but we
advise that the Agency should:
(1) not use letters tc re~resent b~e categories unless a descrio-
tive paragraph on t.~e substance is always used in conjunction:
(2) add a table to the appendix of the guidelines showing the
suggested combined weignr-of-the-evidence category for each
possible r:;ermutation or categories of animal aOO human
weights-of-evidence; ctnd
(3) clarify that regulator! decisions should not be based
on the classification system alone but will include
consideration of factors such as potential hUITan exposure.
Finally. the insertions added to b~e revised test, including t.~e
Review Group's recOTlTT"emations, make L~e texts.'n'bJard i:1 places, am a
editocial revision for readability ~3 r~CCIT1D2~ced.
final
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III. RECG~ME)jDATICNS FOR S?SC=FIC WORDING CHF~GES
[Insert on page 7, a:ter li~e 4 as a new paragra9h]
o A major G~~ of ~~e approach being advocaced ror risk assessment
is G~e use of a 'Ileight-of-the-evidence !"'ethoc:olcgy. This is
because inadequacies in our knowledge of carcinogenesis preclude
advocatirg a step by step prescriptive "ccok-:xx,k" approach
applicable to all suspect carcinogens. Of necessity, the use of
a Neight-of-the-evidence approach places particular ~phasis on
~~e exercise of scientific judgment in revie'~~ng and selecting
information to be used in either G~e qualitative or quantitative
elements of G~e carcinogen risk assessment process. In selecting
infonnation for inclusion in G~e process, priority will be given to
information validated through replication and peer review. Special
weight will be given to hLlIT'an data when they are available aOO
adequate for pU~J0Ses or risk assessment. Generally, however,
such data are not adequate and it is necessarJ to rely on experi-
rnental data. :'J1en data are selected for use in a risk assessment
frem among Multiple data sources, the basis ror selection or
exclusion of G~e data Nill be explicitly seated.
[Page 8, Section 1I.B.2., insert into line 2]
... "that argue for or against the prediction...,
[Page 8, Section II.B.3., last paragraph, line 4, charge to]
... molecular interactions, biologically effec~ive dose, and
transport in, fate in, storage in and excretion fram the body, as
well as ... ~tabolism should r~ discussed and critically evaluated.
[Insert on, page 9 tefore "6. Lorg Term Animal Studies" (add the followirg)]
o The linplications of information presented in L~is section regarding
shape of the dose-response relationship, biologically effective dose,
saturation effects, L~une system effects, shcrt-term test results,
species differences, etc., should be summariz~j so as to facilitate
G~e interpretation of data fram long-te~ anL~l studies.
[Page g, Section I1.8.4., first paragraph, line 3, aGd]
o These should include interactions with other ch~icals or agents
am wiLf1lifestyle factors, \oklere applicable. Storage in the l:xxiy
and possible rec~'cling should also be consicered.
[Page 9, Section II.R.6., and forllard throughout L~e text, 'Nhere appropriate
begin the subsections of the Guidelines by stati~g]
o "This section of an assessrrent should include
"
. . . . , . , , , , . . ,
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rD~re 9 ~~~~~~-rn ~ -'r:p 3 ~~~.1
L"'--':j , -G_......",:=_.:1~:~ -", .:.....-.-- . c.;.;.L;,U.J
. .. ?cwe'le!:", lac:, or :os i ti'.'e !:"eslll:s i::
toxici ty do nct, jy t.:;ansel 'Jes, tJ!:"~':i.::e
pas i tive !:"esu1 ts in a..r:bal ~ioassai's.
S~.0~ ter:-:
a jas is for
tes:s for genetic
di3C8unting
[Page 10, Paragraph 1, line 9, delete]
. .. "Df the sc:ne '''':Or;i:01cgic rIp::. "
[Page 10, Parcgraph 1, line 11, aCc]
... sa1ignant :'~rs, in GCS: cases
:':-.e evidence will l:€ cons idered . . .
[Page 10, last paragrapn,
references to]
13: sentence, at ~,e end of ~~e sentence add
o (NTP, 1984) (L::"'~ 8re=-m.ble).
[Page 11, paragraph 1, line -~,
<:''12r:ge tc ~
. .. high ex-;:csu!:"es a1 ':er t'...."mr res:::c~..ses :JY l7echani~ t.'1at may be ...
[Page 11, paragraph 1, :ine ~S, changes tD]
. .. la..;er e:ccS'..l!:"es s:-.cu1d be ...
(Page 11, paragrap~ 2, _ine ~, char:~e to]
... and llr91ar.:a:icn s:te sarcorcas.
[Page 12, paragrap~ 2, ::ne :, w~a~;e toJ
o To evaluate ca!:":in~enicity, t.~e p!:"~~a~:, c~8arison is tw~or
response i:1 r::CSe-:: ani.-.als as Ccmp2!:"eC -..;i::h t..':1.at in conte!T'~rary
matched control ani.~als. HistOric :cncr~1 r~ta are orten valuable,
however, and...
[Page 12, 2nd para;rapr., e~= or last sentence, add reference to]
o (mP, 1984)
[Page 12, paragraph 2, ~ir:e 3,
c~an;;e to ]
. .. grOl[J ;7',a':, :-e-2c:r€ ::'Jestic:':2Dle
[Page 12, paragraph 2, :ine :0 cha:x;e to]
.., an unusual ~a::~~rc~nd i~ci=ence
(::T? ,
198~) .
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[Page 12, last para~ra9h,
lille S, acd 1
o (Hase~n, 1984)
[Page 13, replacing lir.es 3 & ~]
... classificaticn could be ~an;eC 2n 2 22Se-sy-case basis ~~
"lirnited, II if ',.;arr-anted by the avai2.able ::1foI'-.a.tion on each spec:i.c
substance. Fa~ors to ce taKen in~~ 2C22U:1~ in b~is ce~e~.lna~:cn
could incluce: G'1e cccurrence of t'....-:-crs ...
[Page 13, paragraph 1, line 8 delete]
"showing no e'lidence of metastases cr
in'.l2.sion: '1
[Page 13, paragraph 1, line 9, replace wiL~]
,.. turrors:
[Celete]
"the occurrence of excess turrors only as a sin;2.e sex.
[Page 13, paragraph 2, acd at the beginning]
o All bioassay data are :0 be considered ::1 L'1e evaluation of carcine-
genici ty.
[Page 13, paragraph 2, line 3, delete1
"... that are essentially identical ::1 all ot.her resp:cts to a fDsitive
study,.,"
[Page 14, Section II, 8.~., ;aragraph 2, line 6, 2han;e to]
.., ca~ses of nor~:dity and ceath, and ~e 2C'Ner to cetect an effec:.
The pG'.ver of stucies shculd be included ::1 t..r;e asses~,ent.
[Page 15, 2nd paragraph, line S. change to]
. . ," available
evisence
including eXDCsure
2t3.."
[Page 16, Md]
. .. Cateqorj -: - :-.~ eat3
[Page 17, Add at bottom]
. .. (5) no da ta
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[ Page
18, SEc~:on I~. J.,
paragraph 2, line 9, restore]
Grcu;;s 0 are .:: generall v weuld net
have. . .
[Page 20, paragra9h 1, line 6, change to]
... uncertainty, ~y be useful, for exa~ple, in setting
priori~:es and E2r evaluating ...
regulat:Jrj
[Page 21, SeCtion II:. ~.1., paragra~h 1, li~e 3 change to]
... to ~~e scientists doing the ...
[Page 21, Section III. A.l., paragra~h 2, line 4, add at t~e end]
However, boL~ es~~~ates should te presented.
[Page 21, 1Pr~ra~h 2, line 15, chan;e to]
... human sensiti'lity may be rare or less than the most ...
[Page 23, paragra9D 2, ~ine 16: Add]
. .. "ITechanis:ns 0: t..~e carcino;enesis process are largely unknown and
data are generally limited.....
[Page 23, paragra?n 2, line 19, change to]
... L~e sane carcinogenic processes ...
[Page 24, paragra;;h 1, line 9, change to]
In L~e absence of information to the contra~l ... employed.
apprcpriate, the results of..."
hhere
[Page 24, paragra;;h 2,
of the 2nd paragraph,
paragraph) ]
line 1, replace fir3t rNO sentences (The r~ainder
:Jeg i ,min] .. I n certa in cases..." becanes a neN
o It should ':e em;;hasized that L~e linearized multi-stage mooel leads
to a plausible upper limit to the risk that is consistent wiG~
widely accepteri nechani~s of carcino;enesis. However, such an
estimate does nce necessarily gi'le a realistic prediction of t.~e
risk. The true value of the risk is uncertain, and for ~any
substances ~~e l.:;',.,'er hound estimate of risk is zero. The Aqency's
procedures lead to a range or risk, defined by the upr:;er limit
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estlinate fran the li~ear:zed ~ulti-stage ~ccel are a lO'Ner limit,
'~ich should be explicitly stat9d. An established procedure that
is applicable to a variety of sLDstances does not yet exist for
makirg most likely or best esti.,"":1ates of risk within t...~e range of
uncertainty defined by the upp:r ard lower limit estimates. How-
ever, on a case-hy-case basis 'Nhere the data and procedures are
available, the ~ency will strive to provide most likely or best
estlinates of risk for use in risk management. This will be ~ost
feasible when h~an data are available and wnen exposures are in
the dose range of ~~e data.
[Page 26, paragraph 1: .CoCd]
... Regardless of the classification of a carcinogen, EPA should
evaluate the available data on human and envirormental exposure.
[Page 26, line 3 from bottom, change to]
... fran all relevant sources of exposure including multiole
3venues of intake fram the same source.
[Page 26, last sentence]
... .am rrodeling. TI',e data aOO methods by 'Nhich doses to the target
organ are calculated should be described and critically evaluated.
[Page 27, paragraph I, line 6, change to]
... recommended as an appropriate ...
[~age 27, paragraph 2, l:ne 6, add to the end of paragraph]
Subpcpulations ',oJi t.'1 heightened susceptibili ty (either because-of
exposure or predisposition) should, when possible, be identified.
[Page 29, change the current 3 to 4, and add a new 3 called Host Factors.
Genetic, sex, health or age related factors known or believed to influence
susceptibility should also be taken into account.]
[Page 29, Section III.C.3., after line 8, add]
o In presenting ~Jantitative estimates of risk and wnere sufficient
data are available, it will he appropriate to provide the results
of se~sitivity analyses of ~~e various selected mcdels used to:
calculate risk. Such an analysis requires an explicit statement
of the assumptions and selected parameters used in the l""Odels ann
will aid in identifyi~ the influence of changes in the ass~otions
and parameters. This approach clarifies those assumptions and
parameters that are ~ost significant in influencing the final
risk estlinate values.
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- 9 -
~Page 32: footnote: delete]
... life-threatening benign tumors.
~Page 35, line 16, ~ange to]
. .. used for cgent (s) wi th equivocal or inadequa te human and
animal evicence of carcinogenicity. Inadequate animal evidence
may result :rom animal tests that are technically flawed or when
there is a si~cle negative aniITal bioassay.
:?age 35, line 18, chan;e to]
Group E - No ?csitive EviCence of ...
Group F - No data available
-------
?~~~~-=- ~::- ~-:::= ~-=-~ ~~T...J-=-~~;::~:IC=~!
G.7::C:E:":: ~~S
FEi!.::"l G?DJP
~.e ?e'lie~ ~~~~~ :c~~c E?A's ~roposed Guicelines for Mutagenicity ~isk
.::sse::S':)2nt to t">2 '..;ell reSe2rC"-led and canmends the staff who prepared them
:~r. ~oing a Lioro~gh :00 i~ presenting L~e scientific issues associated
~l~~ assessing t~e risK 0: envirc~ental mutagens, discussing the approaches
for ~litative and ~antitative risk est~tion and in addressing the
~a~cr areas of scienLi=:::: concern and uncertaincj-
-~G~ough it ~as ~ot a major area of disagre~ent, L~e Review Group
:"'as ;-repared, for ~9ncy cons icieration, a rank orcieriry of studies to te
1...:5e-:: in L'1e -n'€i~ht-8:-evicence cetermination of cualitative risk. The
;;;r~csed rankin;;, i:1 ~~::::al oreer, deals wiL~ -test attributes that EP.1I..
s:--.c'-..:..lc use to define :..~e 19vels of evidence relating to human mutagenicity
ix:.::::ee by a c:he-n.ci2J.(s). These eight r-ankirq le'lels include:
1.
Pssiti':e'da~a d2r:.ved f:cem hur.an germ-cell mutagenicity studies,
-~en availa81e, ~ill corstitute the highest level of evidence
f~r h~an ~~tag€nicity.
2.
Valid j;X)sit:.-:e results fran st'Jcies on heritable mutational
events (of any kind) in mammalian germ cells.
~
<
- .
',-slid pes i t:-:e results fran fT'arnmalian ge!JTl-cell chranoscme
acerratien s~~dies that do not include an intergeneration test.
~ .
Sufficient ~:idence for a chemical's interaction with mammalian
germ cells, ~8geL~er with valid positive mutagenicity test results
f:cern two assay ~vstems, at least one of 'Nhich is mammalian (in
vi tro or i:l '::'10). The p...,""'Sitive results may both be for gene
mutatiors or ~t~ :or chranosome aberrations: if one is for
gene mutaticcs 2::C the oL~e~ for chromos~e aberrations, both
~ust ~ Eron ~~'81ian systems.
:J .
Suggestbe 2"idence for a chenical's interaction with marmnalian
germ cells, :~e~,er wiL~ valid positive mutagenicity evidence
::c~ CNO assay systems as described under 4 above. Alternativp.ly,
positiv~ ~ut~er.icity evidence of less strength L~an defined
under ~ ajove, ~nen combined with sufficient evidence for a
c~~ical's interaction wiL~ ~ammalian geun cells.
r
'J .
Positive ~utagenicity test r~sults of less strengt~
under ~ abcve, cG7'bined '~i th sugestive evidence for
interaction Nit~ ~~lian germ cells.
than defined
a d1eo1ical' s
...
.. .
Although de:ini:::,','e pracf of nOffilutagenicity is not p:Jssible, a
~emica.l coulc :e classified operationally as not a human germ-c211
muta;en, if :.: ji-/-=s valid negative test results for all er'iCp:Jints
of concern L~at are enumerated in the guidelines.
3.
Inaeeq\.J.3.L9 e::.c~r.c2 b8arirg on either mutagenicity or chen.ical
interaction '..;it.-~ :'""a-n.!T'alian germ cells.
-------
- 2 -
In addition to L"tis nnking system for e'.'alu2ting evidence fer
mutugenicity, the Revied Group mace several recommendations relating to
OG~er aspects of the guidelin~s. These inclcce:
. EPA sheuld include additional references wiL~in the guidelines
pertinent to established and accepted genetic-risk estimation procedures
that specifically deal with L~e characteriz2tion of L~e human disease
burden introduced by an increase in mutation.
. The Ai;ency
specifically detail
brief discussion of
ability of data for
should modify L~e section on testing systens to more
existing m~lian germ cell tests and provide 3
L~eir strergths are wea.k:nesses and the limited avail-
certain tests.
. The quantitative risk section should
data derived fram exposure, exposure rate and
clesely simulate the h'...ITcBn eXp2rience.
~lace greater emphasis 0n
or other regir:lens t.'1at most
The Review Group recognizes a numeer of research areas that,
pursued diligently, cmld prO/ide the ';'~ency ',vi c~ needed tools to
huwan genetic risk more adequately. Although net exhaustive, the
issues deseDle attention:
if
assess
follof.oJing
1.
More experimental -,....ork on mamrralian oocyte resp::mse to mutagens,
in a variety of experimental mammalian species.
2.
Enhancing the attempts to correlate ~@Th~lian ger.n and somatic
cell mutagenic data with equivalent h~n somatic cell data
in an effort to predict imuced hurnan ;;er.n risk. 'These studies
should utilize same well-defined mutagens.
3.
Further studies employing dominant ~utant phenotypes (e.g.,
skeletal and cataract) that cculd be used in both sexes and
bebNeen different mammalian species. Such studies would improve
the confidence in interspecies extr2polation to man. ~oreover,
additional work needs to be done to ~aracterize the mutation
component of these Genetic endpoints.
4.
Continued development of aneuploidy technology
both sexes and partic~larly in mammals wit.~ an
imprO/ing quantitative risk est~ation.
in Qerm cells of
a im toward
5.
Studies that will better define L~e baseline incidence or hunan
genetic disease ard the mutational canr.::onents associated '.-Ii th tIle
various subcategories or disease determ.ined by various genetic
mechanisms .
-------
- 3 -
6.
More experimental studies
of exposure are needed in
provide needed models for
on varying exposure regL~es and rat2S
eukargate test syst~ in oreer to
extrapolation to IaN dcses.
The RevieN Group concludes that G~e scientific adequacy of the proposed
Guidelines for Mutagenicity Risk Assessment accurately reflect G~e state
of the art of this field. W:! have presented the A:]ency staff 'Hi t.'l a
series of minor changes in the document that we believe will improve the
clarity and general intent of t.~e guidelines. Since these are noted in
G~e transcript of the meeting, we do not intend to specify a line-by-line
edi tirg but note that the staff is in general agreement: wi::..~ these charges.
-------
REFORT Cf THE C>iE:.EC;r. :H:Z~CP~S G_7EEL=~;ES 2EiI:::':'! G?CCP
Intrcduction
. The proble~ of assessir~ health risks of exposure to ch~ic=l ~ixt~res
7s a very linportant issue for the Agency. In te~ of public C2~C~~, ic
1S one of the highest priorities in public health, highlighte-j :::./ r..~e
reactions of communities 1~pacted by-hazarjous waste dump sites.
(,lost envirormental ex::osures are to mixt:J.res rat..'1er than to s:mle
chemicals. In a strict se;'se, it is ccr~ect to G~ink of all ex~cs~es
as eXIDsures to canplex !'1ixt'Xes of cheTlical are phvs ical factors, varic01e
wiG~ time and interacting in complex ways. FOCJsinQ regulatorj a~tenticn
on single ch~.icals results frem ~anv cractical consirleratiors jut teres
to overslinplify t..~e problem of asses~i~g healt..'1 risks.
This is the Agen~i's first attempt to cevelcp guicelines :or ~isk
asseSSIT€nt of chemical mixtures. It is a good first effort, but should
c€ considered only as a ste~ in t..'1e evolution of guidelines 'Nhich shoulc be
revised and i~proved as more scientific info~tion on interactior~ becomes
available and as risk assessors evaluate their experience pericdically.
The proposed guidelines submitted to L~e Review Group were released
for public canr.-em: on Januarj 9, 1985. .~ inter:1al ~ency worx.in;; '7cu;J
has reviewed G'1e public cannents submitted by ['larch 11, 1985, but it has not
had time to incorporate d1.anges in a revise0 set of guidelines. ==='.; staff
will consider t..'1e comments of the present Review Group and of t..'1e ~ublic
for preparation of a new draft. 'The RevierN Group expects that L~e revised
document will be submitted for its review.
Conceptual Framework of L~e Guidelines
The Review Group considers the conceptual framework of t..~e c'-.:r;:-ent
guidelines to be scientifically scund. It notes t..'1at t..~e concept~a:
issues on which these guidelines are based are very different frc~ L'1OSe
of other risk assessment guidelines, for example, those which address
health effects such as cancer.
The RevieN Grcup also reccgnizes L'1at there is a relati'.'e1.y :-eager
data base on the healt..'1 effects of chemical Mixtures and little ex;erience
in preparing these kinds of risk assessments. Scientific eval~aticn or
pctentially adverse health effects of chemical mixtures is an 3re2 of
toxicology that has not undergone extersive research am testirg e:'G'1er
in humans or in laboratorj an i.rnals. Furt~erTI'Ore, such researc.~ a:;d
testing is canplicated by G~e number aro 'lariety of different C'.e-'1ical
mixtures encountered, ei t..h,er l.8n-,nad-e or those that occur natt.:rall? In
addition, when interactio~s of ~ore than tNo ch~icals are stt.:di2:-
systematically, the complexity of experL~ntal design is increased and
the size of the project and t~e ccsts can increase eno~Dusly.
Although not a matter of conceptual frame'NOrk, the guideli~es would
be better understocx:J. and TOre easily used by risk assessors ard G-:e DubEc
if they were substantially re<.«itten. Information on potential uses. of
the guidelines wculd be hel~ful to irxJbiduals outside t..~e A:;ency. ~l..:i7'ercus
reviewers have noted the absence of any definition of chemical mixtures.
A few examples are given, but no limitation is placed on what might
constitute a complex mixture. There is also no recognition of L~e temcoral
component of expcsures to mixtures. I~ several ~3rts of ~~e dcc~~nt -
nore care is ~eeced in ~~?cise ce:i~it:c~ cf teC?~:Gc~c~y~
-------
?eC:C'r.Tr.e!:da tion
The c~rrent proposed guidelines should be revised addressing c~~r.ts
rece ive-j at and since t..'1e March ~, 1985 Dreliminar( lCleet:.n:;; of L'-le Re'Jie.oJ
Gr::up as ',veil as L'10Se received fran the- April 22-23, 1985 rreetirg. T"lis
redraft should be reviewe-j by mail bv t:,e Review GrouD at wnich ti~e L~e
need for further r~JieN ~ill be considered, including-the possibility of
resubmission for public comments.
Scientific Issues
1.
Issues relating to L'1e guidelines' s~ri in Table 1 (page ~171)
The pror;osed guidelines recccnize L'1at L'1e arount and tVDeS of data
a'vailable on a dlenical mixture m~y varv considerablv. The "i:-~camnendaci.on
is to enphas ize "flexibility, judgment ~nd clear an:iculation of the
ass14""TIptions am liMitation in any risk assessment." EPA staff have
incorporated a table summarizing L'1e proposed ap9roach to chemical mixcures.
The Review Grrup found this tabular s1..!I11T!E.ry helpful rut has several
suggestiors intended to increase its utility. These inc~ude:
o
The concepts in Table 1 should be presented in flaw chart form
such that L'1e decisions to be rnade at each brandl point are
illustrated, the consequences of that necision made explicit
and, if possible, t.~e data needs articulated. The table Eornat
doos not allow for recycle locps or multiple options if appro-
priate. This revision in format could also reflect the differences
in the quality of available information where one set of decisions
are clearly data-based and anOL'1er are highly inferential.
o
In the text or in an appendix, EPA should provide illustrative
examples of how the guidelines would be used. ~ese examples ~ould
be drawn fran actual cases per:ormed by the .2>q'ency or would be
sllnulations designed to elucidate the procecure. I~ has bee~
noted elsewhere in L'1is report L'1at L'1e guidelines contain too
few examples. This table (or chart), \vhic~ for some readers
will be the only L'1irg they read, '''''ould tEnefit Eran such an
illustration.
o
The Re\!,iew Group found that not all L111;;ortant outCO"1es '.vere
accounted for in the table. It reccrnmends that the flow chart
or c~parable device be expanded to include additional options.
For example, where more than one outc~e is of importance to C;8
risk manager, the interaction or such outcomes should be indic~ted.
This interaction could involve carcinogenic and systemic toxicity
erx:Jpoints or mutagenic ard Cevelopmental effects.
In the evaluation of "sufficient 5 bilad ty," there is L'1e need fo!:"
~':e guidelines to recognize that this concept cc.:uld be defined in terms
of composition (e.g. an homologous series of hydrocarbons) or in terms of
ere-effects (e.g. a series of Central Nervous Syst~ depressants such as
alcohols, ketones and simple esters).
The importance of ex;;::osure c'.ata in identifyirg am qU3.ntifyirg risk
is not integrated into the proposed scheme. Such data are needed for G~e
~roper ~se of Step 3 which deals wiG'1 indices of acceptable ex;;::osure.
-------
-
r.1cst llnCO rt 3:1 tl V, t..'1e!::"e should 2e a ':::-=.nc;"', :..n :..'-":e .:ec:..s :"2:-', - -',~ J,.~
'Nhich leads to a ":1e~detinable !::"isk" eu~.::::r,e. -=:-:e :=,2'lio2-'" c;:-:::c;: '::-2':":"2'-es
t..'1at conditions C3n exist in which t..':.ere =.re no ,::)x:..ci :.~,. Ca.:'3 3\-32- :212
on the chemical mixtures; there is no "Si...:.::iC:"2:-,~l'/ s:":7\il3.:-" :-,ix:.-~e
;..hich has h~en St-l1d~ed. "'r-p n,rrnh.o..,... 01..': Ui,.,i,~pn-i':~'='~-~""""--"""en-c: ;:: '",,""""~
~':'L '-- - , w.- \.JJ.l~- .----i.1'-.....__,-......... I.-....A..~.l .._~ ....- --"-"';:--
am/or t..'1e amount or data on the few ide:1~:..:iaJ':"e c:::r-.::anent.s :..S ~aL.
In such instances, hazard identification, ~~e =.c:~ow19c~~ed ::..~t. st.~;: ~~
risk assessrrent, is not pJssihle. C:Jnsec-...:..enc:.'-:, ':~,e cecis :..::::;n ::::-:::cess .=:-"ould
Trove to a "non-definable risk" outcc:::m:::. --=:-:e a~':e'!:":1ac::le is 3.:1- 2.sses~ent
with such wide uncertainty bards as to te :-ea.ni~less O!::" "islea'::':-J:;.
2.
Greater ~phasis on levels
of c~~:cpnce in risk asses~nts
The scientific basis for estiJ".ati:-'.C :,,'-":2 r:sks of C:'1E!'"',ical :-.:x~'~e.s is
highly variable der:ending ufXJn t..':.e tyr:e-c: :;ix':~e, :"'le ccr.;Jlex.:.:.::.' 0: :':-_2
mixture, ard data availability. A risk =.s:=es~nt ::ased u;on :::"-:3.Ssay
data for the mixt~e in cuestion, for ex~le, ::robablv has a ~u.~ hi~.e!::"
degree of confidence aSsOciateci with it t.'":an cC€S a risk asseS2"€:1t ::.2se-j
upon the toxicity of some of G':.e comDOnen~ of a JJCrlv-characte!::":.z~~
:'1ixture. There is a neeri to express. G"le-:8<:::-ee e~ c::-nf idence to ~
associated wi~~ various risk asses~ncs ~:-~~ical ~ixtures. ~cC8r::~ly,
tl1e Revier,.; GraJp recamrerds that the <;uiCe2.i.nes be re'Jised ':~ Ce'.'elcp ::...--C
incorporate a system to express the level ~: cc~ridence aSSOC:3te~ ~i~~ a
risk assessment. Such a ~jstem Might, fer ex~~le, :e anal~eus :'2 L~e
L~C classification system for carcino<;er.s, -Nhi,~ sL~3rizes ~~e ~Bi~~~
of evidence for carcinc:genici ty of a C1E!:':Cal.. ~Ie ce
-------
- 4 -
based upon qualitative or suggestive data. Variatiors i~~erent in single
chemical risk aSSGSSiT'ents should also te covered by the sensitivity
analyses; these variations incluce the use of alternative data sets, extra?-
alation f~~ different species, use of alternative pathology results, use
of confidence intervals ar~ alternative exposure levels.
3.
Need for a tedinical supI;X)rt docurr.ent
The technical and scientific background from 'which these guidelines
must draw their validi ty is so broa
-------
- 5 -
o
Is L~e~2 a L~eor2tical or practical lL~it to L~e
in a dcse a:iditi.ve mccel?
nurn.t:er cf
e.gent:s
o
Role of Gatrix sersitivity--toxicity of an agent may 2e a Eunc~:on
of oG~er agents =eing present.
o
Cri teria am rreL'1ods for evaluation of data quality.
o
Kelationship between rrechanisms of inte~actions and ~chani~ of
toxici 1:'1.
o
Research r.eeds
.Jther Issues
1.
Identification of research needs
Although G"le toxicity of chemical mixtures has been recognized for
~ecades as an linportant area for toxicolcgic research, there has te9n
little emphasis on this area until recently. Consequently, G~e existence of
large gaps in available infor:nation is not surprising. The RevieN' Grcu;J
jelieves L"lat an linportant mechanism for identifying c~itical research
:-:eEds is inherent in Lf1e process of carrying cut risk assessrrents. The
Jffice of Research and Ceveloprnent should ensure that there is an effecr ive
linkage wiL~ the research planning process to take full advantage of
~"lese opportunities.
The preparation of L"le tec."lnical support
~any research needs, 'Nhich likewise should be
:he research planning process.
docJlcent will also identi:y
made available and utilized in
2.
Cse of case-by-case approach.
AB irdicated in t!1e guidelines and else'.vnere in this report, the
~asis of scientific information is VeDj meager for quantitative risk
asses~nt for exposure to multi-component Mixtures, with the exception
~f a few complex single source emissions or products (such as coke-oven
exhaust, gasoline, PCBs). Consequently it is appropriate, as L"le guidelines
suggest, to ~ very flexible in approaches to risk assessment. The RevieN'
Sroup suggests that risk assessrrents of chemical mixtures be done on a
c:ase-by-case basis, until a substantial background of experience is buEt
~p in this area.
3.
"Enshrining the uncertainty"
The guidelines thenselves, and to a greater extent this RevieN' Group
report, have emphasized the need to specify t.~e level of confidence (or
:.:egrees of uncertainty) in various steps of the risk assesSITEnt. The
Keview Group believes L~ese estimates should not only be a component of
::..~e risk asS€ssrrent but should be carried forward throJgh all steps in
L"le risk 8anagement process and be made a part of releases of infor.nation
to L~e p~~lic. The RevieN' Group indentifies the objective of this process
to be "enshrining the uncertainty."
-------
-'
~lerall scie~ti=ic 3c~~acy or the Risk Assessment Guidelines for Chemicc~
~.' ixtures .
'I1",e ReviE"N Gr:::L:p ":Jelieves it would te inapprcpriate to state a
c8nclusion on sc:e~tific adequacy at this time, inasmuch as the draft
c~idelines are in ~~e crocess of revision. The document was on a different
schedule by several '~~ks, and the closure of public comments did not
cCOJr until ~1arch :1, 1985. The EPA workirg group is already preparirg a
reviseC draft, ~ased on the public comments, Agency comments, and L~e SAB
:-:-€etirr;;s of '.!ar::1 .:, am April 22-23. EPA staff anticipate carlpletirg the
r~vision wiG~in a;~rox~ately 30 days and has asked the Review Group to
c-:msider the revis-ed draft. This will te done by mail ard by a conference
call; ano~~er meet:n~ will be held if deemed necessary after the conference
c 3.11.
The Review Gr=up believes that present operational guidelines for
~,~ical mixtures s~ould continue to be used as interim guidelines.
The technical supr:oct document should te subni tted to the usual
;~r review process for technical documents and should be submitted to the
S.;B for revieN. ~.e S;'.3 should evaluate the doct.IT!1ent in terms of its suit-
~ility as su~port :~r G~e chemical mixtures guidelines, and should
reccrnmend 'Nhet..'1er :.'"'.e draft supPJrt document should be made available for
;~lic carment.
-------
RS:C?i OF T-}E CEVELDPMDIT..:lJ., ITFECIS ':;UICELINES REV--r:::";.j G..~C(jP
Scientif:c ?~equacy of the Guidelines
The RevieH Group ccncludes L~at, i~ general, the prcposed guidelines
are scientifically adequate and ccmITensurate with the ~resen~ scate of
the science. However, the field of developmental toxicology is particularly
weak with respect to quantitative aSSeSSIT€nts. The guidelines could be
improved by revisio~£ in L~e section relating to L~e relaticnships of the
maternal toxicity in comparison to toxicity for the fetus. ~e bases for
quantitative assessrrent also require elaboration. The Review Grcup
requests responses from the Agency on G~e specific points raised and the
opfXJrtuni 1:-j to revieH a revised draft at 'Nnich t:ir-e 'He 'Hill render a
final opinion.
General Conclusions
The prcposed Guidelines for the Health Assessment of Suspect Develop-
mental Toxicants are generally well wri:ten and appropriately express
the kinds of actions which are fXJssible, given the present state of the
art. Ce'leloprrental toxicity studies ha'le largely addressed qualitative
resfXJnses, and the guidelines reflect L~is situation. ~kst or the testing
methodologies employed at present are not as readily adaptable to quanti-
tative assessments, esr:;ecially wi L~ res;:ect to chronic ex"[X)sures.
Specific Issues
1.
Inteqration With Other Guidelines
The Review Group understands that L'Le gulcelines for reproductive
effects that are not maternally r.ediated are still under cev8lopment. It
is also clear that many instances will cc:::ur in wnic~ it will be difficult
to differentiate beDveen paternally mediated effects, effects originating
during fertilization, maternally mediated reproductive effects and di~ect
effects on the fetus. As EPA develops L'Lese additional guidelines for risk
assessment it should integrate them wic1 L~e existing guidelines as they
evolve.
2.
Definitions
The RevieN Group briefly discussed cBfinitions used in L'Le proposed
guidelines and concurred that the concept of "functional develop-nental
toxicology" was useful. However, it also noted that the well-established
concept of "teratogenicity" appeared to be subsumed under other definitions
and concepts in a number of instances. EPA neerls to make distinctions
in the definitions and use of these concepts.
3.
Qualitative Assessments
The possible number of aiverse effects in reproductive toxicology,
in contrast to the possible number of out2omes in carcinogenicity testing,
is very large. Consequently, the probabili ty of miss ing an adverse effect,
because it was not anticipated in L~e experimental design, is a ~uch more
likely event. This fact introduces complexities into the assessment of
developmental toxicity that EFA should keep in mind.
-------
-
I': the avaEable anL-rnal data indicate t.l1at a substance disr.Jpts
deve1q:::rnent only at 1'1atemally toxic dcses, and if ex;:osl::-e IX'tential fT1aY
also include G~e maternal toxic dose range, G~en the substance merits
careful scrutiny and is a possible candidate for additional study.
In evaluating dcse-related effects obse~led in maternal and developing
organisms (at any dcse used), it is important to apply judgment as to t..l-)e
comparative nature and severity of these effects. Moreover, effects in
the developing organism in the presence of maternal effects shoul~ not
necessarily be corsidered secondary effects or of lesser significance in
evaluating developmental toxicity.
The proposed guidelines emphasize G~at the responses in the most
appropriate and/or sensitive scecies should be used in risk asses~nt.
The Review Grouo suaaests t..~at-the most aoorooriate soecies be determined
on the basis of-1'1et~olic and pharmacokin~tic- charact~ristics with direct
bearing on the toxic mechanism in t.l1e experbmental organism in comparison
to h 1...Il1Bns .
EPA should evaluate functional tests in assessing developmental toxicity
on the basis of sensitivity of such tests to subtle toxic effects, the
recognition that functional tests may assist in interpreting the biological
significance of other effects of exposures, and the fact that data obtained
fran human fOpulations have sometimes indicated functional OOfici ts. For
example, behavioral testing in animals may also be useful in assessing
questions of toxicity to the nervous system.
The Review Group expresses concern about t..~e use of screening tests for
developmental toxicity. It endorses the use of single high dose screening
studies for the purpose of prioritization (as developed by Chwernov),
with reserJations. Panel members share the concern of several previous
cammenters that materials found to be positive in this screening test
might be r:;ermanently labelled as "teratogenic" by t.l1e public at large, a
label which we consider to be possibly premature in some i~stances since
the test is likely to produce a relatively high number of false posi~ives.
Although we believe that it is desirable that screening tests produce
very few false negative responses, and thus are bound to produce false
positive responses, the tendency to place bnmediate labels on the pcsitive
responders is unfortunate and unjustified in some instances.
The Review Group also considered the possible utility of structure-
activity relationships in screening new chemicals for possible developmental
effects. Structure-activity relationships, although potentially useful,
are not sufficiently advanced at this time to be generally useful
even for prelDninary assessments, with the possible exception of prelDninaDj
assessments of hormone analogs.
4.
Ouantitative Assessments
On theoretical grounds, in most cases a t..l1reshold should exist for
developmental effects in terms of the dose required to elicit toxicity.
However, there is not a sufficient basis to rule out t..~e possibility that
non-threshold MOdels may he more appropriate for some endpoints of certain
toxicants.
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It is i'C1portant to reccxmize L'-J.at b~e No-Observee-;::.::fect-Level (~OEL),
\c~:2served-Adverse-Effect-Level (~AEL) and Lowest-ocSerleG-Effect-Level
(LOEL) approaches attempt to approximate an apparent c'-J.reshold region
L'-J.at incorporate judgment as part of the q~antitative a~prcach. However,
the presence or absence of a threshold is, at present, almost linpossible
to ascertain, and that an exact threshold cannot be readily determined 2y
:'1athematical inference. The mere existence of an :-J'OEL neit.'-J.er proves r.or
disproves the existence of a real c~reshold. An experL~entally determined
010EL is not necessarily at or below a t.~eshold dcse are, in that context,
it is important to examine the qJantitative relationshi~s of ~OEL dose
rates to dose rates that result in effects. The exa~ination of t.~e
effects needs to take L'-J.e t~~ of severity of the effect into account
including the dose rates at which t.~ey are elicited. The a9plication of
a safety factor or an ~~certaintv factor to an ~CEL mav still result in a
res idual risk. - -
In some instances it may he necessarJ to conduct a reanalysis of
experimental data to determine whether the conclusions drawn by the
authors of a study 'M9re valid, es~cially ....nen the original tyr:;es of
statistical analyses seen to have been inappropriate, or ~nen the reported
statistical Oltcanes do not seen to be supported by the data.
The Revie'll Group considered ,...nether EPA should introduce a 'Heighting
factor into the range of adverse cutcanes L~at could result fran ex;:osure
to a developmental toxin. The consensus opinion was that the state of
the science was not sufficiently developed to ~nable a determination of
the relative i.r!1portance of structural abnomalities, altered growth,
functional deficiencies, and intrauterine death; the considerable
uncertainties in extrapolating from one such effect to anot.~er, as well
as fran species to sp:=cies for a gi'ven effect, was also noted. For hU:"En
data, such determinations extend oeyond the area of risk assessment into
the risk management area. The qcestion of malfomations versus anatomic
variations was also discussed. The Re'liew Group believes t.'-J.at, althout;.'1
the significance of anata~ic variations is at present not well under~tcod,
a dose related increase in their incidence should be taken into acco~~t
in the risk assessment process.
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REroRT CF THE S~::.B EX~FOSlJRE fI.5SESS-'1ENT (-UIDELINES REV:;:2,.J GRCUP
The proposed G~idelines for Exposure ~;Ssessment provide a very good
statement on L~9 general principles of exposure assessment ~~ logical
procedures to follow in the absence of reliable measur~ent data on
exposure. ~e specific ccmments 'Nhich relate to the discussion on
uncertainty are offered in a later section of this review and should he
considered in L'l.e revisions aoo corrections that were given to EP.A.. staff
during the course of G~e review.
Despite G~e generally satisfactorJ conditions of G~e ~aterial
included within the proposed guidelines, the Review Group concludes L~at
it is unsatisfactor.1 to entitle L'l.em as G'1e EPA 's "Guidel ines for Exposure
Assessment" because they give virtually no guidance on L'1e uses of environ-
mental measure!'.ents for e~[XJsure assessment. Sane of the SPA program
offices ~ake extensive usage of measurement data in their exposure assess-
Ments, and quite prC9€rly so. Agen~l-wide guidelines should certainly
ackncwledge such usage and encourage more of it. The Review Group was
unanilnous in concluding that direct measurements of concentrations of
[XJllutants in air, water, food, and soil, made with suitable sampling
protocols and quality assurance practices, usually proTide better indices
of h~an exposure than theoretical models. A secondary benefit in the
use of this approach to eXj;XJsure assessrrent is th.at aCCL...."1\ulated data can
provide a basis for the valid~tion of exposure models.
The prcposed guidelines appear to have teen written fran the per-
spective that exposure assessment should depend primarily on MOdels,
supplemented when [XJssible by measurements of the characteristics and
strengths of pollutant sources such as stacks, discharge pipes, fugitive
industrial emissions, and waste dumps. They give virtually no recognition
to more directly relevant environmental media at the receptors. Specific-
ally, the guidelines state (page 46307) L'1at "The analysis of monitoring
data should be considered a complement to environmental paL'l.Way and fate
analysis..." They devote space to a general discussion of environment.al
fate, transport and transformation, and identification of principal path-
ways of eX[XJsure. However, not until the last sentence on ~~onitoring
(page 46308) is an acknowledgement nade that "Reliable, analytically
determined values should be given precedence aver estimated values ~enever
significant discrepancies are found" (between model and measurement data).
The RevieN Grrup believes that measurements provide the best basis for
exposure assessrrent, and L~at modeling should be used only 'Nhen there are
too limited nUITDers and/or inaccuracies in available measur~ents.
The RevieN Group unanimously concludes that the guidelines will only
be partially complete until they are expanded to include a whole new
section on the general principles of the measurement of [XJllutant concen-
trations in the various environnental media. Furthermore, the preface to
L'l.e existing proposed guidelines should indicate that environTental
measurements, Yrhenever feasible should have precedence aver estimates
based on theoretical or 6'1pirical models. wnere a limited a.mount of gCOd
enviromental rreasur6T1ent data are available aOO need to be exparxied wi L'1
rrodelled exposures, b~e measurements provic1e a means of Guiding the
selections of model input parameters which can give a greater degree of
confidence in the model predictions. The guidelines should also address
the limitations of environmental concentration data for exposure assessment.
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- 2 -
A section should be added ~nich delineates erY~~ 2~cc~"tereri
representativeness of ~~e samples, sa~pli~ err::r, l~~r~torj
errors, and data maniDulation errors. It shoulc 3150 discuss
bevNeen precision and- accuracy.
suc~
3.S :..-.e
analys!.s
the di::ere~ces
The supI;XJrtirg docw'T:entation for t..'1e prcpcsEd ?Jidelines nO'N inc2.:"::::2s
a background paper using TCDD as a ~odel for ex=csure assessment. ~.:s
provides a good example of how one can proceed to ~ake an exposure assess-
ment in the absence of relevant data. The doc~,entation for the fi~32.
guidelines would benefit fram the inclusion of tHO other examples as ~Bll.
One should be for a r:ollutant for which a relat.:.ve '..;ealt.'1 of enviro~ental
exposure data are available, such as carjon Monoxi~e or lead. .;nother
should be for r:ollutant for which a limited ~unt of data are avail~~e,
e.g., benzol or arsenic.
The proposed guidelines have not sp2cified t.~e form of the output to ::e
generated from the ex!;X)Sure assessment. \tie recCJ:"'T.1end t.~at a specific :c~
of the output be proposed, such as an esti~ted exposure distribution,
specific of each target population, supplemented by appropriate indic3.~:c~s
of t.~e uncertainty (-e.g., confidence limits), for ~~e esti-nated distr:::ut:.::n
function.
When combining estDmated exr:osures across 113ricus scenarios, the
association or correlation among the various components needs to be acdressed.
1;m.en eealirg with synergistic responses in tt1e ccmbined risk asses~m:
context, the association or correlation &~ng L~e agents needs to be ~:::dressed.
In slIIT1r!B.ry, the Review Group finds that t:'1e pr-=90Sed guidelines ;::-::"JiCe
a very good overliew of general principles to je followed in measuri~
pollutant concentrations in environmental ~dia. ~c~ever, in their ;resent
state, they fail to sufficiently emphasize t.~at ex;csure assessr.-ents :~ed
on reliable measurements of pollutant concentratior.s in environmentaI' -.:-dia
should take precedence over exposure estimates based on unvalidated ~0Cels.
In addition, they fail to provide guidance on ~le general principles :0 je
followed in measuring pollutant concentrations in envirorITental media. ~~ese
critical deficiencies need to be properly addressed jefore they can Oe
recommended for approval as Agency-wide Guidelines for Exposure .;Sses~nt.
At ~f1e same time, Pgency staff should proceed to finalize ~f1ose sectL:::.s c:
the guidelines t.~at state gener~l principles of exposure assessment ar~
procedures to follow in the absence of me~surement data, following f,-=:':~er
consultation with the Review Group.
In discussing the report of t..~e Review Group ~~e SAB Executive C~.i~:ee,
by majority vote, further recommended t.~at: 1) L~e ;reface of the Gui=2~:~es
be revised to emphasize that direct measurements, :..tlenever feasible, :-.3'Je
procedence over estinates based on unvalidated ~els as the basis fc~ ~~e
Agency's exposure assessments; 2) t.~e revised guidelines, '.J1ich shoul<~ incl'..,:.::e
the neN preface ann the corrections resulting from L~e Review Group a~d 8~lic
c~nts, be retitled to indicate ~~at it represenLs general guida~ce ~0j
procedures to be followed when direct measurements are not feasible, ~~c to
indicate that they are not overall guidelines for eXDCsure assessment; and
3) that the Agency commit itself to the preparation,- on a priority tasis,
to the preparation of a guidelines document on the ;erformance of expcsure
assessments based in whole, or in part, en direct ~:easureTIents of pol:~:ant
concentrations in er.viror.mental media.
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- 3 -
Specific Ccrrrnents on Uncertaintv
1. We canmeoo Dr. vhitnore's ',.;ork on the uncertainty analysis which
is utilized in the proposed guidelines. The analysis is useful
where environmental measurements are not available or feasible,
and exposures and eXDOSure distributioD£ need to be assessed
using a theoretical ~del.
2. An important conponent of uncertainty t..'1at is not sufficiently
addressed is uncertainty about the for:n or the ITDdel, i.e.,
systematic error or bias arising fran the use or a mcdel. vhen
environmental measurements are available, t..'1e validation of t..'1e
model can be used to detennine b'1e presence and magnitude of
systematic errors. When exposure measurements are not available,
sane subjective judgrrent 'tlill be needed.
3. Another important can~nent of uncertainty is the random error
not pre
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u. s. ::::i'.ll::?C0~'1E~lAL P?L'r:::C':'IOJ .;GENCY
Science Advisor] board
Risk ,\ssess;-;-ent Guidelines' Reliew Groups
Dr. Norton Nelson (Chairman)
Professor of Envirormental ~Iedicine
Institute of Environmental Medicine
New York University Medical Center
500 First Avenue
New York, New York 10016
Carcinoaenicitv Guidelines Review GrouD
~ ~
Dr. Richard A. Griesemer (Panel
Director, Biology Division
BoxY
Oak Ridge National Laboratory
Oak Ridge, Tennessee 37830
O1air)
Dr. Roger o. McClellan
Director of Inhalation Toxicology
Research Ins t i tute
Lovelace Biomedical and Environmental
Research Institute
P. o. Pox 5890
Albuquerque, New Mexico 87185
Dr. Frederica Perera
School of Public Health
Division of Environmental
( 8-10 9 )
Columbia University
60 Haven Avenue
New York, New York 10032
Sciences
Dr. Norton Nelson
Professor of Environmental Medicine
Institute of Environmental Medicine
New York University Medical Center
500 First Avenue
New York, New York 10016
Dr. Terry F. Yosie
Director, Science Advisor] 30ard
U. S. Environmental Protec~:on Agenc]
401 M Street, S. w.
Washington, D. C. 20460
IX. Ronald Hart
Director
National Center for Toxicol~ic21
Research
Jefferson, Arkansas 72079
Dr. 'i'larner North
Principal
Decision Focus, Incorporated
Los Altos Office Center
4984 El Camino Real
Suite 200
Los Alto, California 94022
Dr. Henry Pi tot
Director
i~c.Z\rd Ie Labora to ry
'* 50 North Randall Avenue
!vlad ison, Wiscons in 53706
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- 2 -
Mutacenicitv Guidelines Review GrOUD
- ~
Dr. Se:/ffiOur Abrahamson
Professor of Zoolo;;y and
C€partTent of Zoolcgy
University of Wisconsin
Madison, ';'jisconsin 53706
Genetics
Dr. Rotert Neal (Panel Chair)
President, C~emical Indust=y
Institute of Toxicology
P. o. Box 12137
Research Triangle Park, NC 27709
Dr. ~ichael Shelby
National Institute of Envirormental
Health Sciences
Post Office Box 12233
Research Triangle Park, N. C. 277ng
Dr. i~arv Esther Gaulden
CepartmEmt of Radiology
University of Texas Health
Science Center--Dallas
5323 Harry Hines Blvd.
Dallas, Texas 75235
Dr. Liane Russell
Section Head
Biology Division
Oak Ridge National
Post Office Box Y
Oak Ridge, Tenn.
Laboratory
37831
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- 3 -
Chemical Mixtures Guideli~es Review Grc~~
Dr. John Coull
Professor of Pharmacology and
Toxicology
Depart.'CEnt of Pharmacology
College of Health Sciences
and Hasp i tal
The Universibj of Kansas
39~~ and Rainbow Boulevard
Kansas Civj, Kansas 66103
Dr. Robert Scala
Exxon Corporation - REHD
Post Office Box 235
:-1etlerl s Road
East Millstone, New Jersey
08873
Dr. Ronald Wyzga
Program Mana;Jer
Electric Power Research
Institute
3412 Hillview Avenue
Post Office Box 10411
Palo Alto, California
9430 3
=-:-. C,arles Reinhardt
=i~ector, ~askell Labora~c~!
::)r 'I'oxicology and
I~~~strial Medicine
:: I c'.J Font de NE?"'\Ours am Canpany
=:l:.cto:1 Road
'~'.-oiar:<:., Delaware 19711
:r. Jar:1eS ~'l1i ttenberger (Panel Chair)
~i~ector; Southern Occupational
:':022- th Center
19"722 ~'acAr"'"J1ur Blvd.
:"-:-ti'lersity of California
:;::-line, CA 92717
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- 4 -
Develq::mental Effects GuiCe1ines Revie'N Grou:J
Dr. Larrj Fechter
Kresge Hearing Research Institute
Univers i ty of j'!ich igan !1edical School
1301 East Ann Street
Ann ArOOr, Mic!'1igan ~8109
Dr. Rolf Hartung (?anel C~air)
School of Public Health
University of Mi~igan
Ann P'.rOOr, Midligan -18109
Dr. Marshall Johnson
Department of Anatcr.1y
'Ihares Jefferson Cniversi ty
1020 Locust Street
Philadelphia, PA 19107
Dr. Ellen Silbergeld
Chief Taxies Scientist
Environmental Defense fund
1525 18th Street, )J. :'1.
Washington, D. C. 20036
Dr. ~v:.c Ccylcr
Di'lisic:i 0: 3i:::r.'2t::-'.:-
National Cente~ :or
:oxicological ~ese3rch
Je::ersc!1, .~kansas 72079
Dr. ~c:1ald D. ~ccd
?!:"c:esscr, Cevelq:x:>e!'1tal 3iolO9Y
Sec~ion, ~;:.ar:;:;e!1t of Biolo;JY
Cn i'le rs i t'/ 0 E _~1&.~aJT'.a. a.rC
?!:"i!1ci:::al Associate, R. J. Hood
am .;;Sscciates
Corsulcing Toxicologist
Pose Office Box 1927
lini':ersi,:y, Alabama 35486
Dr. Susan Siet:e!:"
Nat:.cnal Ca.ncer Instieute
9000 Rockville ?ike
Bui:::in; 31 ~0CJ'1 l:l..~J 3
8et.'-cesca, \jary12nd 2'J 20 5
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- 5 -
Exposure Guidelines Review Group
Dr. Richard CUddihy
Senior Scientist
Inhalation Toxicology
Research Institute
Lovelace Biomedical and
Environmental Researach
Post Office Box 5890
Albuquerque, New Mexico
Institute
87185
Dr. Thanas Ki ttleman
Loubiers Building
13W10
Dup:mt Company
~-1ilmirgton, Delaware
19898
Dr. JerrJ ~~solowski
California Department
2151 Berkeley Way
Berkeley, California
of Health
94704
Dr. Naihua DJan
University of WiscQnsin
Math~tics Research Center
1S10 Walnut Street
r'1adison, ~visconsin 53705
Dr. Morton Lipr:mann (Panel
Institute of Environmental
Medicine
Lanza Laboratory
Long Meadow Road
New York University
Tuxedo, New York 10987
Chair)
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