April 10, 2015
Agency for Toxic Sub
bstances an
nd Disease Registry
gy and Huma
an Health Sc
ciences
Division of Toxicolog
Environm
mental Toxicology Branc
ch
1600 Cliffton Road, N.E.
p F-57
Mail Stop
Atlanta, Georgia 303
333
Re:
Supplement to Co
omment on the Draft Toxxicological Profile for Trichloroethyle
ene,
(October 2014)
To Whom
m It May Con
ncern:
The Chemica
al Products and Technology Division
n (CPTD) of the America
an Chemistryy
Council wishes to supplement its
s March 16, 2015 comm
ment on the October 2014
4 draft
Toxicolog
gical Profile for Trichloro
oethylene (T
TCE) with the
e enclosed summary tab
ble comparin
ng
the candidate studies
s for develop
pment of min
nimum risk levels (MRLss). As noted
d, these stud
dies
were identified in the
e 2011 Integrrated Risk In
nformation S ystem (IRIS
S) Assessme
ent for TCE1
develope
ed by the U.S
S. Environm
mental Protec
ction Agencyy (EPA) as th
hose genera
ating the low
west
e reference concentratio
ons (RfCs) fo
or critical he
ealth end poiints. ATSDR
R has proposed
candidate
to adopt the RfC sele
ected by EPA
A as both th
he intermedia
ate and chro
onic MRL witthout conducting
its own ro
obust review
w of the available studies
s. The attacched table ca
an assist the
e Agency in
conductin
ng this revie
ew as require
ed by ATSDR’s authorizzing legislatio
on.2
In
n addition to providing su
ummary info
ormation for each of the studies, the enclosed ta
able
assigns a Klimisch sc
core for the reliability of the study da
ata and the rational for that score. As
you are no doubt aware, Klimisch et al. (1997)3 develope
ed the scorin
ng system as a means to
he reliability and relevan
nce of data from toxicolo
ogy and ecottoxicology sttudies. The
assess th
Klimisch system is in
nternationally
y recognized
d and is wide
ely used in the review off substancess
under the
e Registratio
on Evaluation Authorizattion and Resstriction of Chemicals (R
REACH)
egulatory pro
ograms. Th
he use of the
e scoring too
ol allows the
regulation and other European re
available
e studies to be ranked ba
ased on form
mal criteria u sing interna
ational stand
dards as
reference
es. It allows
s for subsequ
uent focus on the most r elevant and
d reliable (i.e
e., highest
quality) studies and health endpo
oints, while not excluding less reliab
ble data that may help to
o
support these data.
1
EPA. Toxicological Review for Trich
hloroethylene: In Support of Summary Inforrmation on the Integrated Rissk
Inform
mation System (IRIS). EPA/63
35/R-09/011F. U.S. Environm
mental Protectio
on Agency, Wa
ashington, DC
(2011)).
2
42 US
SC 9604(i)(3).
3
Klimisch H et al. A sy
ystematic appro
oach for evalua
ating the qualitty of experimen
ntal toxicologica
al and
ecotox
xicological data
a. Regul Toxico
ol Pharm 25:1-5
5 (1997).
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e
April 10, 2015
Page 2
Such ranking of studies is
s a critical part of the syystematic revview of subsstances that was
a central element of the recomm
mendations frrom the National Researrch Council (NRC)4 for
g federal risk assessment programs
s such as the
e developme
ent of ATSD
DR’s
improving
Toxicolog
gical Profiles
s.5 NRC ma
ade the recommendation
n to addresss repeated prroblems
g within IRIS
S assessmen
nts, such as the 2011 Asssessment fo
or TCE upon
n which
occurring
ATSDR’s
s proposed MRLs rely. In stressing the importan
nce of such a systematic approach,
NRC exp
plains that ­
th
he systematiic review pro
ocess is und
dertaken to id
dentify all re
elevant literature on
he agent of interest, to evaluate the identified stu
udies, and possibly to provide a
th
qualitative or quantitative
e synthesis of the literatu
ure.6
While the
e NRC’s reco
ommendatio
on did not co
ome in time t o benefit the IRIS Asse
essment for TCE,
ATSDR has the oppo
ortunity to in
ncorporate th
he Council’s advice and the experien
nces of the
al Profile for t he substancce.
European Union in updating its Toxicologica
Based on CP
PTD’s evalua
ation of the candidate stu
udies identiffied by EPA, only one ca
an be
considere
ed reliable without restriictions (Klimisch score 1
1) – the study by Woolhiser et al. (20
006)
which pro
ovides data on observed
d changes in
n kidney wei ght and imm
munosuppresssion resulting
from TCE
E exposure. As noted by EPA, this study is an O rganization
n for Econom
mic Co-operation
elopment (O
OECD) guide
eline immuno
otoxicity stud
dy performed
d in accorda
ance with Go
ood
and Deve
Laborato
ory Practices
s (GLP) published by EP
PA for the To
oxic Substan
nces Control Act.7 As a
result of its conformitty to nationa
al and interna
ational stand
dards, the sttudy by Woo
olhiser et al.
(2006) prrovides the most reliable
e data on wh
hich to base the MRLs.
Six additional studies of those identified
f
by EPA as candidate
es can be co
onsidered
reliable with restrictio
ons (Klimisch
h score 2), primarily beccause they do not appea
ar to conform
m to
GLP. Th
hese studies report neurological, live
er, immunolo
ogical, reproductive, or developmenttal
effects as
ssociated with exposure
e to TCE in la
aboratory an
nimals and, in the case of the study by
Ruijten et al. (1991), in humans. The studies
s also can sserve as a re
eliable basis for establish
hing
the MRLs
s, taking into
o account an
ny additional issues thatt may impactt their releva
ance or
sing human exposure to TCE.
adequacy for assess
The remaining nine studies8 should be considere
ed unreliable
e (Klimisch score 3) beca
ause
y design, documentation
n, and/or rep
porting or because of concerns abou
ut the
of flaws in their study
interpreta
ability of the results. It is
s of considerable conce rn that this group includes the studie
es
A used to dev
velop its RfC
C and, as a consequence, that ATSD
DR uses as a basis for its
that EPA
proposed
d MRLs.
4
5
NRC. Review of the Environmental Protection Age
ency's Draft IR
RIS Assessmen
nt of Formaldeh
hyde. Washing
gton,
DC. National Academ
mies Press (2011).
System
matic evaluatio
on also is consistent with ATS
SDR’s draft Guiidance for Prep
paration of Toxxicological Profiles.
6
NRC 2011, at 154.
7
EPA 2011, at 5-15.
8
The IR
RIS Assessmen
nt does not pro
ovide enough in
nformation on tthe rat study byy Frederiksson et al. (1993)
referen
nced by EPA to
o allow an evalluation of its re
eliability.
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chemistry.com® 700 Seccond St., NE | W ashington, DC 20002 | (202) 2449.7000 ACC CPT
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e
April 10, 2015
Page 3
The first of these studies (NTP 1988)), used by EPA as a sup
pporting evid
dence for its RfC,
cannot support mean
ningful interp
pretation of the reported kidney effects as a resu
ult of significcant
s in the docu
umentation of animal bre
eeding, anim
mal identity, clinical obse
ervations,
breeches
environm
mental condittions, and an
nalytical che
emistry data reported in an audit of the in-life po
ortion
9
udy. Althou
ugh these fin
ndings are de
escribed in N TP’s Techn
nical Report, they are no
ot
of the stu
discusse
ed in the drafft Toxicological Profile or the IRIS Asssessment.
The second key study ide
entified by EPA and ATS
SDR is the study of imm
munological
effects co
onducted by
y Keil et al. (2
2009) which
h reports a dose-related effect in botth thymus we
eight
oimmunity in mice exposed to TCE. In characterrizing this sttudy, EPA no
otes that the
ere is
and auto
“greater than usual uncertainty” associated with the RfC
C developed from this stu
udy for
autoimmunity, but tha
at it is the “o
only suitable study” for c alculating an
n RfC for efffect on thym
mus
weight. Of concern is that Keil et al. (2009) found that th
he immunolo
ogical effectss were more
e
pronounc
ced in B6C3
3F1 mice, wh
hich are not particularly s usceptible to autoimmu
une disease,
he autoimmu
une prone sttrain of NZW
WBF1 mice w hich were also exposed
d. The IRIS
than in th
Assessm
ment suggestts that the re
esults reported by Keil e
et al (2009) “a
are not nece
essarily
discordant” with the results of oth
her studies -- including a finding of no effect on thymus weig
ght
in rats re
eported by Woolhiser et al. (2006) -- but attemptss no explana
ation of the apparent
incongruent findings.. The draft Toxicologica
al Profile, on the other ha
and, is silentt on the mattter.
The final stud
dy identified by EPA and
d ATSDR is t he study byy Johnson ett al. (2003), the
focus of ACC’s origin
nal commentt, which repo
orted fetal he
eart malform
mations in ra
ats. Among the
concerns
s that have been expressed about th
he design an
nd methodology of this study are the
e use
of nonconcurrent con
ntrol data an
nd the poolin
ng of control data, the an
nomalous exxposure­
response
e pattern, an
nd the failure
e to report da
ata other tha
an that for ca
ardiac defeccts. In
m this study,, and earlier studies from
m the same authors, NR
RC noted tha
at ­
considering data from
th
he rodent stu
udies showin
ng trichloroe
ethylene-indu
uced cardiacc teratogene
esis at
lo
ow doses we
ere performe
ed by investigators from a single insttitution. Also
o noted
were the unusually flat do
ose-respons
se curves in the low-dose
e studies fro
om these
in
nvestigators.. . . Thus, the
e animal datta are inconssistent, and the apparen
nt species
ave not been addressed
d.10
differences ha
The spec
cies differenc
ces remain unaddressed
d, despite th
he eight yearrs that have passed sincce
sed its conce
ern. Althoug
gh the draft Toxicologica
al Profile ackknowledges the limitation
ns of
NRC rais
the study
y by Johnson
n et al. (2003
3), it conclud
des that “in t he absence
e of convincing information to
ort of trichlorroethylene-induced card
diac malform
mations in ratt fetuses is
the contrrary, the repo
considere
ed valid and
d relevant to humans.”11 As noted byy NRC and California’s Office of
mental Health Hazard As
ssessment (O
OEHHA),12 h owever, the
ere are confflicting data from
Environm
9
NTP (1988). Toxicolo
ogy and carcino
ogenesis studies of trichloroe
ethylene (CAS No. 79-01-6) in
n four strains of rats
(ACI, August, Marsha
all, Osborne-M
Mendel) (gavage
e studies). Tecch Report Serie
es No.273. Nattional Toxicolog
gy
Progra
am, Research Triangle Park, NC. NIH Publ. No. 88-2525.
10
NRC. Assessing the Human Health
h Risks of Trich
hloroethylene: K ey Scientific IIssues. Washin
ngton, DC: The
e
Nation
nal Academies Press (2006), at 171.
11
ATSDR. Draft Toxico
ological Profile for Trichloroeth
hylene (Octobe
er 2014), at 138.
12
OEHH
HA. Public Hea
alth Goals for Chemicals in Drrinking Water – Trichloroethylene. Office of Environmentall
Health
h Hazard Asses
ssment, Sacram
mento, CA (Jully 2009).
americanc
chemistry.com® 700 Seccond St., NE | W ashington, DC 20002 | (202) 2449.7000 ACC CPT
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hloroethylene
e
April 10, 2015
Page 4
well-cond
ducted studies by Fisherr et al. (2001
1) and Carne
ey et al. (200
06) that thesse organizattions
considere
ed convincin
ng evidence to the contrary.
r
As described above, and in the enclo
osed table, s ystematic re
eview of the reliability off the
m studies ide
entified by EPA as candiidates for de
eveloping the
e RfC for TC
CE, and
data from
considere
ed by ATSD
DR for establishing MRLs
s, indicates t hat there arre several sttudies that a
are
clearly prreferable to those studie
es selected by both EPA
A and ATSDR
R. These sttudies provid
de
values fo
or the inhalattion MRL tha
at range from
m 0.001 to 0 .910 parts per million (p
ppm) with
multiple studies clusttering around 0.01 and 0.1 ppm. W e urge ATSD
DR to condu
uct a system
matic
mmended by
y NRC, priorr to finalizing
g its MRLs fo
or TCE.
review off these studies, as recom
Please feel frree to contac
ct me at [email protected], or att (202) 249­
6727, if you any ques
stions aboutt the enclose
ed informatio
on.
Sinccerely,
Steeve Risottto
Step
phen P. Riso
otto
Senior Director
Che
emical Produ
ucts and Tecchnology Divvision
Enclosurre
cc:
H. Abadin, En
nvironmenta
al Toxicology
y Branch
americanc
chemistry.com® 700 Seccond St., NE | W ashington, DC 20002 | (202) 2449.7000 Lowest Candidate Reference Concentations (RfCs) for Critical Effects
(from Table 5‐24 of the 2011 IRIS Assessment for Trichloroethylene)
Health Endpoint
Species
Neurological effects
Cognitive effects (Isaacson et al. Rat
1990)
Mood and sleep disorders (Arito Rat
et al. 1994)
Human
Trigeminal nerve effects (Ruijten et al. 1991)
Kidney effects
Toxic Neuropathy (NTP 1988)
Rat
Response 1
Rate
Candidate RfC (ppm)2
Uncertainty Factor3
Drinking LOAEL
water
Inhalation LOAEL
‐‐
0.007
1000
3
‐‐
0.016
300
2
Inhalation LOAEL
‐‐
0.530
10
2
0.0006
10
3
0.002
300
3
Pre‐GLP, poor documentation, excessive mortality
Pre‐GLP, high response rate
Route of POD type
Exposure
Notes (quotes are from IRIS document)
Non‐GLP, concerns about study design
Non‐GLP, exposure characterization "less reliable"
Non‐GLP, small sample size
Gavage
BMDL
Mouse
Gavage
LOAEL
Meganucleocytosis (Maltoni et Rat
al. 1986)
Kidney/BW ratio (Woolhiser et Rat
al. 2006)
Liver effects
Liver/BW ratio (Kjellstrand et al. Mouse
1983)
Immunological effects
Thymus weight (Keil et al. 2009) Mouse
Gavage
BMDL
BMR=10%
0.003
10
3
Non‐GLP, high response rate
Inhalation BMDL
BMR=10%
0.001
10
1
OECD guideline study conducted to GLP
Inhalation BMDL
BMR=10%
0.910
10
2
Non‐GLP
0.0003
100
3
0.001
30
Non‐GLP, autoimmune‐prone mice less sensitive than B6C3F1 mice
Non‐GLP, study conducted in auto‐
immune prone mice
Non‐GLP, transient response during exposure
OECD guideline study conducted to GLP
Toxic nephrosis (NCI 1976)
Drinking water
BMR=5%
Klimisch Score4
‐‐
LOAEL
‐‐
Autoimmunity (Keil et al. 2009)
Autoimmunity (Kaneko et al. Mouse
2000)
Immunosuppression (Sanders Mouse
et al. 1982)
Immunosuppression (Woolhiser Rat
et al. 2006)
Inhalation LOAEL
‐‐
0.120
300
2
Drinking LOAEL
water
Inhalation BMDL
‐‐
0.017
100
3
0.110
100
1
BMR‐1%
Lowest Candidate Reference Concentations (RfCs) for Critical Effects
(from Table 5‐24 of the 2011 IRIS Assessment for Trichloroethylene)
Health Endpoint
Reproductive effects
Hyperzoospermia (Chia et al. 1996)
Fertilization in vitro (DuTeaux et al. 2004)
Sperm effects (Kumar et al. 2000; 2001)
Developmental effects
Congenital effects (Johnson et al. 2003)
Developmental neurotoxicity (Frederiksson et al. 1993)
Species
Route of POD type
Exposure
Human
Inhalation BMDL
Rat
Drinking LOAEL
water
Inhalation LOAEL
Rat
Rat
Drinking water
BMDL
Response 1
Rate
Uncertainty Factor
0.002
30
3
‐‐
0.009
1000
3
‐‐
0.013
1000
2
0.0004
10
3
Non‐GLP, control data pooled over an extended time period, only heart data reported
0.160
1000
4
IRIS document provides no discussion of Frederiksson study in rats
0.062
100
2
Non‐GLP, "well‐conducted study" but insufficient detail on experimental methods
BMR=10%
BMR=1%
Rat5
Resorptions (Healy et al. 1982) Rat
Inhalation LOAEL
Klimisch Score3
Candidate RfC (ppm)2
‐‐
Notes
Non‐GLP, exposures reported in ranges
Non‐GLP, insufficient exposure period
Non‐GLP, "well conducted study"
POD ‐ point of departure; LOAEL ‐ lowest observable adverse effect level; BMDL ‐ benchmark dose lower bound (95% CI); BMR ‐ benchmark response
1
Indicates the reponse rate for which the BMDL is calculated.
2
Using EPA's preferred dose‐metric.
Composite uncertainty factor used to calculate the candidate RfC.
4
Klimisch scoring (Klimisch et al. 1997): 1 ‐reliable without restictions, 2 ‐ reliable with restrictions, 3 ‐not reliable, 4 ‐ not assignable. Klimisch scoring is a standard method used by the European Union for assessing the reliability of toxicological studies. Studies with Klimisch scores of 1 or 2 are used to assess an endpoint. Klimisch score 3 data can be used as supporting information. Scoring is based on CPTD's evaluation of the information available for the study. 3
5
Although Table 5‐24 lists information for a rat study by Fredericksson et al. (1993), the IRIS document only discusses a study with mice.