United States
Environmental Protection
1=1 m m Agency
EPA/690/R-07/018F
Final
9-11-2007
Provisional Peer Reviewed Toxicity Values for
Gadolinium
(CASRN 7440-54-2)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw
body weight
cc
cubic centimeters
CD
Caesarean Delivered
CERCLA
Comprehensive Environmental Response, Compensation and Liability Act

of 1980
CNS
central nervous system
cu.m
cubic meter
DWEL
Drinking Water Equivalent Level
FEL
frank-effect level
FIFRA
Federal Insecticide, Fungicide, and Rodenticide Act
g
grams
GI
gastrointestinal
HEC
human equivalent concentration
Hgb
hemoglobin
i.m.
intramuscular
i.p.
intraperitoneal
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
i.v.
intravenous
kg
kilogram
L
liter
LEL
lowest-effect level
LOAEL
lowest-observed-adverse-effect level
LOAEL(ADJ)
LOAEL adjusted to continuous exposure duration
LOAEL(HEC)
LOAEL adjusted for dosimetric differences across species to a human
m
meter
MCL
maximum contaminant level
MCLG
maximum contaminant level goal
MF
modifying factor
mg
milligram
mg/kg
milligrams per kilogram
mg/L
milligrams per liter
MRL
minimal risk level
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
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PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
GADOLINIUM (CASRN 7440-54-2)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
This document has passed the STSC quality review and peer review evaluation indicating
that the quality is consistent with the SOPs and standards of the STSC and is suitable for use by
registered users of the PPRTV system.
INTRODUCTION
Stable (nonradioactive) gadolinium is the subject of this issue paper. No toxicity or
carcinogenicity assessments of gadolinium are available from IRIS (U.S. EPA, 2007a), HEAST
(U.S. EPA, 1997), or the Office of Water (U.S. EPA, 2007b). Gadolinium has not been
evaluated by ATSDR (2007) or IARC (2007), or tested or scheduled for testing by NTP (2007).
No occupational exposure limits are recommended or promulgated for gadolinium by ACGIH
(2007), NIOSH (2007), or OSHA (1989, 1993).
This issue paper is based on information obtained through comprehensive searches of the
following databases in 2007: TOXLINE (1965-2007), CANCERLINE (1970-2007), MEDLINE
(1966-2007), GENETOX, DART, CCRIS, CHEMID, RTECS, EMIC, ETICBACK, and
TSCATS. Extensive tree-searching of acquired literature was performed to identify pertinent
data from the older literature.
REVIEW OF PERTINENT LITERATURE
Human Studies
No human studies were located regarding exposure of humans to gadolinium.
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Animal Studies
Oral Toxicity Data
Groups of 6 male and 6 female rats (strain not reported) were fed 0, 0.01,0.1, or 1%
dietary gadolinium chloride (98% pure) for 12 weeks (Haley et al., 1961). Compound intake is
estimated to be 9.1, 91, or 935 mg/kg-day (5.4, 54, or 558 mg Gd/kg-day) in the males, and 10.0,
100, or 1001 mg/kg-day (6.0, 60, or 597 mg Gd/kg-day) in the females. These intake values
were calculated using reported body weight data (from growth curves) data, and food
consumption estimates based on an allometric equation relating food consumption to body
weight (U.S. EPA, 1988). Body weight was measured biweekly throughout the study, and
hematology (total erythrocytes, total leucocytes, differential cell count, hemoglobin, and
hematocrit) and histology (heart, lung, liver, kidney, pancreas, spleen, adrenal, and small
intestine) were assessed at the end of the study. Exposure-related changes in liver histology were
observed in the males at 558 mg Gd/kg-day. The liver effects consisted of perinuclear
vacuolization and coarse granular cytoplasm in parenchymal cells in 6/6 of the high-dose males;
these effects were "not regularly observed" in the lower dose male groups (incidence data not
reported) and were absent in females. Liver pathology findings in controls were not reported but
incidences are presumed to be 0/6 in each sex. Although the liver pathology findings suggest
adverse effects at the high dose in males, the data are insufficient to clearly discern the threshold.
A 10% reduction in body weight gain in males exposed to the highest dose (558 mg Gd/kg-day),
reported in the earlier PPRTV draft, could not be verified because Figure 1 in the Haley et al.
(1961) study clearly shows that the lower body weight was associated with the lowest dose (5.4
mg Gd/kg-day). The male rat body weights at the two higher doses were indistinguishable from
the control weights. Nothing in the study text helps determine whether the Figure 1 legend
contains a typographical error or which dose caused the effect. Assessment of the body weight
data is further complicated by the lack of a dose-response and by a magnitude (-10% decreased
weight gain) that is imprecise due to estimation from growth curves and not unequivocally
adverse. Assessment of the liver pathology data is complicated by the small group sizes,
unreported incidences in the control, low- and mid-dose groups, and possible adverse effects in
the low- and mid-dose groups as indicated by observations of liver lesions in some of the
animals. These insufficiencies in the body weight and liver pathology data preclude clearly
identifying a NOAEL and LOAEL from this study.
Inhalation Toxicity Data
CFW mice were exposed to 0 or ~ 30 mg/m3 concentrations of gadolinium oxide (Gd2C>3)
aerosol (99.9% pure, mean particle diameter 0.312ja, 17.9 mg Gd/m3) for 6 hours/day, 5
days/week for 20, 40, 60, 80, 100 or 120 days, and observed for duration of natural life (Ball and
VanGelder, 1966). The numbers of animals in the control and exposed groups ranged from 6-10
and 20-30, respectively, and were equally divided by sex. Hematology (total and differential
leukocyte counts, hemoglobin levels, packed cell volume, and clotting times) was assessed in
20%) of the surviving mice at the end of each exposure period and at 12 and 18 months after the
start of the study. Following natural death all animals were necropsied and histologically
examined (unspecified representative tissues). Average lifespan ranged from 7.8-19.7 and 9.2-
13.3 months in the groups of control and exposed mice, respectively. Mortality from pneumonia
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was increased in most groups of exposed groups of mice but not related to duration of exposure;
the overall average mortality in the exposed mice was 22% compared to 14% in controls. Most
of the pneumonia-related mortality occurred 2-5 weeks after exposure started. Calcification in
the lung occurred in 32-95%) of the groups of exposed mice, but in none of the controls; the
overall average percentage of mice with pulmonary calcification was 54.8%. The incidences of
pulmonary calcification were not clearly related to duration of exposure. Fibrosis was noted
rarely in the lungs of the mice exposed for shorter durations and occasionally observed in the
120-day exposure group; incidences of fibrosis were not reported. The severity of the lung
pathology and consequent mortality indicates that 17.9 mg Gd/m3 was a frank effect level (FEL)
in mice.
Pulmonary toxicity was evaluated in groups of 6 male and 6 female guinea pigs who
were exposed to Gd203 aerosol in concentrations of 0 or 20 mg/m3 (11.9 mg Gd/m3) for 6
hours/day, 5 days/week for 40, 80, or 120 days (Abel and Talbot, 1967). Most (92%) of the
particles were <0.563[j, in diameter. Pulmonary function (elasticity determined by compliance
measurements on excised lungs) and lung histology were assessed at the end of the exposure
periods. A highly significant (p<0.01) linear trend in the exposed groups indicated that lung
elasticity decreased with increasing duration of exposure. Histopathologic changes in the
exposed lungs became more severe as exposure time increased and included alveolar cell
hypertrophy, septal cell wall thickening, nodular lymphoid hyperplasia, and macrophage
proliferation. These pulmonary effects indicate that 11.9 mg Gd/m3 was a LOAEL in guinea
Pigs-
Other Studies
Measurements of excreta and carcass showed that gastrointestinal absorption of
gadolinium as a Gd159-citrate complex was <0.1% in 4 days following an unspecified gavage
dose in rats (Durbin et al., 1956).
An oral LD50 value of >1743 mg Gd/kg was determined for gadolinium nitrate in female
rats that were observed for 30 days following administration (Bruce et al., 1963). Acute
intraperitoneal LD50s of 80 mg Gd/kg for gadolinium nitrate in female rats observed for 30 days,
105 mg Gd/kg for gadolinium nitrate in female mice observed for 30 days, and 328 mg Gd/kg for
gadolinium chloride in male mice observed for 7 days have also been determined (Bruce et al.,
1963; Haley et al., 1961). Symptoms of acute gadolinium chloride toxicity in the mice included
decreased respiration, lethargy, abdominal cramps, and diarrhea (Haley et al., 1961).
Gadolinium has strong paramagnetic properties that are used as the basis of intravenous
magnetic resonance imaging agents (Cacheris et al., 1990; Mann, 1993). These compounds are
stable chelates in which the gadolinium cation is incorporated in polybasic organic ligands, often
polyaminocarboxylate molecules derived from the parent molecule EDTA. The intravenous use
of gadolinium in chelated form is necessary to reduce Gd+3 toxicity and improve its solubility
(free gadolinium ion is readily precipitated in vivo), tissue distribution (precipitates are deposited
in liver, bone, and other tissues), and renal clearance. A number of gadolinium-chelate
complexes have been developed and tested for clinical safety, including gadopentetate
dimeglumine, gadodiamide, gadoterate meglumine, and gadoteridol.
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Groups of 4 male Wistar rats were administered doses of 0, 10, 20, 50, or 100 jag Gd/rat
(approximately 0.04, 0.08, 0.2, or 0.4 mg Gd/kg, based on reported body weight data) as
gadolinium chloride by intratracheal instillation and killed after 2 days (Yoneda et al., 1995).
Other groups of 4 rats were similarly treated with 50 jag Gd/rat and killed at intervals ranging
from 0 hours to 175 days following instillation. There was a dose-related deposition of insoluble
forms of Gd in the lung tissue where the content decreased slowly with a calculated biological
half-life of 136 days (for the 0.2 mg Gd/kg dose); 26% of the initial dose remained in the lung
tissue 175 days after exposure. The Gd content in the bronchoalveolar lavage fluid remained at a
constant level (about 5 |ig) over the 0.08-0.4 mg Gd/kg dose range and was not detectable after
31 days.
The pulmonary toxicity of inhaled rare earth compounds, in general, have been the
subject of debate, especially with regard to the relative contributions of radioactive contaminants
versus stable elements in the development of progressive pulmonary interstitial fibrosis (Haley,
1991; Beliles, 1994). In particular, although it is known that stable rare earth compounds can
produce a static, foreign-body-type lesion consistent with benign pneumoconiosis, there is
uncertainty whether they can also induce interstitial fibrosis that progresses after termination of
exposure. Human inhalation toxicity data on stable rare earth elements mainly consist of case
reports on workers exposed to multiple lanthanides (Kappenberger and Buhlmann, 1975; Husain
et al., 1980; Sabbioni et al., 1982; Vocaturo et al., 1983; Colombo et al., 1983; Sulotto et al.,
1986; Vogt et al., 1986; Waring and Watling, 1990; Deng et al., 1991). Animal inhalation
toxicity data on stable rare earths mainly consist of a few inhalation or intratracheal studies on
some rare earth mixtures and some single compounds (Schepers, 1955a,b; Schepers et al., 1955;
Ball and VanGelder, 1966; Abel and Talbot, 1967; Mogilevskaya and Raikhlin, 1967). A
comprehensive assessment of the human and animal data by Haley (1991) concluded that the
evidence suggests that inhalation exposure to high concentrations of stable rare earths can
produce lesions compatible with pneumoconiosis and progressive pulmonary fibrosis, and that
the potential for inducing these lesions is related to chemical type, physiochemical form, and
dose and duration of exposure.
Carcinogenicity Data
No oral carcinogenicity studies of gadolinium were located in the available literature. A
90-day feeding study of gadolinium chloride was performed in rats (Haley et al., 1961), but it is
inadequate for assessing carcinogenic effects due to insufficient duration of exposure and lack of
a posttreatment observation period.
An inhalation study was performed in which groups of CFW mice were exposed to 0 or
~ 30 mg/m3 conentration of gadolinium oxide aerosol (99.9% pure, mean particle diameter
0.312[j,, 17.9 mg Gd/m3) for 6 hours/day, 5 days/week for up to 120 days, and observed for life
(Ball and VanGelder, 1966). The numbers of animals in the control and exposed groups ranged
from 6-10 and 20-30, respectively. Incidences of primary lung tumors were not increased in the
exposed mice although nonneoplastic lesions occurred in the lungs (see summary in RfC
Assessment). Tumor incidences in tissues other than lung were not reported or discussed.
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An implantation study was performed in which groups of 30 male and 30 female
weanling CFW mice were subcutaneously administered a 200 mg pellet of gadolinium (1.5-2.0
mm diameter) and observed for life (Ball et al., 1970). Comparison with 16 male and 16 female
sham-implanted controls showed no clear treatment-related induction of local sarcomas.
Incidences of implantation-sited sarcomas were 1/30 and 0/16 in treated and control males,
respectively, and 2/30 and 0/16 in treated and control females, respectively. No tumor
metastases were observed. Implantation-site granulomas that were indicative of a foreign-body
reaction developed in treated mice (15/30 males, 18/30 females) but not in controls.
Supporting Data
Genotoxicity and other supportive data relating to the potential carcinogenicity of stable
gadolinium were not located in the available literature.
DERIVATION OF A PROVISIONAL SUBCHRONIC OR CHRONIC RfD FOR
GADOLINIUM
Information on the toxicity of repeated oral exposure to gadolinium is limited to a 12-
week dietary study which found minimally decreased body weight gain and liver histological
alterations in male, but not female, rats (Haley et al., 1961). Inadequacies in study design and
reporting, particularly small group sizes and incomplete incidence data, preclude clearly
establishing NOAELs and LOAELs and possible derivation of an RfD.
DERIVATION OF A PROVISIONAL SUBCHRONIC OR CHRONIC RfC FOR
GADOLINIUM
Limited information is available on the toxicity of repeated inhalation exposures to
gadolinium. Subchronic studies were performed in which mice and guinea pigs were
intermittently exposed to single dose levels of gadolinium oxide for up to 3 months and, in the
case of the mice, subsequently observed for life (Ball and VanGelder, 1966; Abel and Talbot,
1967). Marked pulmonary histopathological changes occurred in both studies with
manifestations that included decreased lung compliance and pneumonia leading to mortality.
Although the findings in these animal studies appear to be consistent with pulmonary effects of
inhalation exposure to high concentrations of rare earth compounds in general, the single dose
levels showing a LOAEL or FEL preclude discerning the exposure-response threshold and
possible derivation of an RfC.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR GADOLINIUM
Weight-of-Evidence Classification
Carcinogenicity data on gadolinium are essentially limited to two studies. Lung tumors
were not induced in mice that were observed for life following subchronic inhalation of a
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pulmonary toxic concentration (single exposure level) of gadolinium oxide (Ball and Van
Gelder, 1966), and subcutaneous implantation of a gadolinium pellet caused no clear treatment-
related induction of local sarcomas or metastases in mice observed for life (Ball et al., 1970).
The lack of additional studies precludes assessing possible carcinogenicity. In accordance with
U.S. EPA (2005) guidelines for chemicals with inadequate human and animal data, stable
gadolinium is assigned a weight-of-evidence (WOE) description of "inadequate information to
assess carcinogenic potential." Consequently the human carcinogenicity of gadolinium cannot
be determined.
Quantitative Estimates of Carcinogenic Risk
Derivation of an oral slope factor or inhalation unit risk for stable gadolinium is
precluded by the lack of adequate studies in humans and animals.
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