EPA/690/R-18/004 | September 27, 2018 | FINAL
United States
Environmental Protection
Agency
Provisional Peer-Reviewed Toxicity Values for
Stable (Nonradioactive) Soluble Lanthanum
(CASRN 7439-91-0)
U.S. EPA Office of Research and Development
National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (Cincinnati, OH)
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A rnA United States
^jup^ Environmental Protection
EPA/690/R-18/004
FINAL
09-27-2018
Provisional Peer-Reviewed Toxicity Values for
Stable (Nonradioactive) Soluble Lanthanum
(CASRN 7439-91-0)
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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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Q. Jay Zhao, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Jeffry L. Dean, PhD
National Center for Environmental Assessment, Cincinnati, OH
Jeff Swartout
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS iv
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 8
HUMAN STUDIES 17
ANIMAL STUDIES 17
Oral Exposures 17
Inhalation Exposures 33
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 33
Genotoxicity 45
Acute and Short-Term-Duration Oral Studies 45
Other Route Toxicity Studies 45
Mode-of-Action/Mechanistic Studies 46
Metabolism/Toxicokinetic Studies 47
DERIVATION 01 PROVISIONAL VALUES 50
DERIVATION OF ORAL REFERENCE DOSES 50
Derivation of a Subchronic Provisional Reference Dose 50
Derivation of a Chronic Provisional Reference Dose 54
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 56
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 56
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 57
APPENDIX A. SCREENING PROVISIONAL VALUES 58
APPENDIX B. DATA TABLES 59
APPENDIX C. BENCHMARK DOSE MODELING RESULTS 71
APPENDIX D. REFERENCES 89
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Soluble Lanthanum
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COMMONLY USED ABBREVIATIONS AND ACRONYMS1
a2u-g
alpha 2u-globulin
MNPCE
micronucleated polychromatic
ACGIH
American Conference of
erythrocyte
Governmental Industrial Hygienists
MOA
mode of action
AIC
Akaike's information criterion
MTD
maximum tolerated dose
ALD
approximate lethal dosage
NAG
7V-acetyl-P-D-glucosaminidase
ALT
alanine aminotransferase
NCEA
National Center for Environmental
AR
androgen receptor
Assessment
AST
aspartate aminotransferase
NCI
National Cancer Institute
atm
atmosphere
NOAEL
no-observed-adverse-effect level
ATSDR
Agency for Toxic Substances and
NTP
National Toxicology Program
Disease Registry
NZW
New Zealand White (rabbit breed)
BMD
benchmark dose
OCT
ornithine carbamoyl transferase
BMDL
benchmark dose lower confidence
ORD
Office of Research and Development
limit
PBPK
physiologically based pharmacokinetic
BMDS
Benchmark Dose Software
PCNA
proliferating cell nuclear antigen
BMR
benchmark response
PND
postnatal day
BUN
blood urea nitrogen
POD
point of departure
BW
body weight
PODadj
duration-adjusted POD
CA
chromosomal aberration
QSAR
quantitative structure-activity
CAS
Chemical Abstracts Service
relationship
CASRN
Chemical Abstracts Service registry
RBC
red blood cell
number
RDS
replicative DNA synthesis
CBI
covalent binding index
RfC
inhalation reference concentration
CHO
Chinese hamster ovary (cell line cells)
RfD
oral reference dose
CL
confidence limit
RGDR
regional gas dose ratio
CNS
central nervous system
RNA
ribonucleic acid
CPN
chronic progressive nephropathy
SAR
structure activity relationship
CYP450
cytochrome P450
SCE
sister chromatid exchange
DAF
dosimetric adjustment factor
SD
standard deviation
DEN
diethylnitrosamine
SDH
sorbitol dehydrogenase
DMSO
dimethylsulfoxide
SE
standard error
DNA
deoxyribonucleic acid
SGOT
serum glutamic oxaloacetic
EPA
Environmental Protection Agency
transaminase, also known as AST
ER
estrogen receptor
SGPT
serum glutamic pyruvic transaminase,
FDA
Food and Drug Administration
also known as ALT
FEVi
forced expiratory volume of 1 second
SSD
systemic scleroderma
GD
gestation day
TCA
trichloroacetic acid
GDH
glutamate dehydrogenase
TCE
trichloroethylene
GGT
y-glutamyl transferase
TWA
time-weighted average
GSH
glutathione
UF
uncertainty factor
GST
glutathione-S-transferase
UFa
interspecies uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFC
composite uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFd
database uncertainty factor
HEC
human equivalent concentration
UFh
intraspecies uncertainty factor
HED
human equivalent dose
UFl
LOAEL-to-NOAEL uncertainty factor
i.p.
intraperitoneal
UFs
subchronic-to-chronic uncertainty
IRIS
Integrated Risk Information System
factor
IVF
in vitro fertilization
U.S.
United States of America
LC50
median lethal concentration
WBC
white blood cell
LD50
median lethal dose
LOAEL
lowest-observed-adverse-effect level
MN
micronuclei
Abbreviations and acronyms not listed on this page are defined upon first use in the PPRTV document.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
LANTHANUM (CASRN 7439-91-0) AND SOLUBLE SALTS
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by at least two National Center for
Environment Assessment (NCEA) scientists and an independent external peer review by at least
three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
Currently available PPRTV assessments can be accessed on the U.S. EPA's PPRTV
website at https://www.epa.gov/pprtv. PPRTV assessments are eligible to be updated on a
5-year cycle to incorporate new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human-health effects and are revised as appropriate.
Questions regarding nomination of chemicals for update can be sent to the appropriate
U.S. Environmental Protection Agency (EPA) Superfund and Technology Liaison
(https://www.epa.gov/research/fact-sheets-regional-science).
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. EPA programs or external parties who may choose to use PPRTVs are
advised that Superfund resources will not generally be used to respond to challenges, if any, of
PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVS
Questions regarding the content of this PPRTV assessment should be directed to the
U.S EPA Office of Research and Development's (ORD's) NCEA, Superfund Health Risk
Technical Support Center (513-569-7300).
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INTRODUCTION
Lanthanum, CASRN 7439-91-0, a member of the lanthanide series, is a metallic element
with an atomic number of 57. Lanthanum salts are used in electronic devices, pyrophoric alloys,
rocket propellants, reducing agent catalyst for conversion of nitrogen oxides to nitrogen in
exhaust gases (usually in combination with cobalt, lead, or other metals), and phosphors in X-ray
screens (Lewis and Hawlev. 2007). Lanthanum is listed on U.S. EPA's Toxic Substances
Control Act's (TSCA) public inventory (U.S. EPA, 2018b) and is registered with Europe's
Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) program
(ECHA. 2018).
Lanthanum occurs naturally in the earth's crust at a concentration of approximately
39 ppm (Bunzli. 2013). Lanthanides, such as lanthanum, typically occur in compounds as
trivalent cations in carbonates, oxides, phosphates, and silicates (t'SGS, 2016). Lanthanum is
found in several minerals including cerite, monazite, allanite, and bastnasite. Monazite and
bastnasite are lanthanum's principal ores in which the element occurs in percentages up to 25
and 38%, respectively (Haynes, 2014). Monazite is digested using caustic soda to obtain the
lanthanides as hydroxides. They are then treated with hydrochloric or nitric acid to remove
thorium and other elements, and finally further processed to recover the individual lanthanides.
A similar process can be used for bastnasite (Bunzli. 2013).
Lanthanum is a silvery-white, malleable, ductile metal that is soft enough to be cut with a
knife. It oxidizes rapidly when exposed to air. Lanthanum reacts slowly with cold water and
more rapidly with hot water (Havnes. 2014). Reaction with water forms lanthanum hydroxide
and hydrogen. Lanthanum metal is soluble in acids (Lewis and Hawlev. 2007). Table 1
summarizes its physicochemical properties. Like other lanthanides, lanthanum forms mostly
ionic compounds, has a high preference to bind to oxygen, and exists in its +3 oxidation state in
compounds or in solution under most conditions. In general, lanthanide salts of chloride, nitrate,
and perchlorate are soluble, while salts of hydroxide, carbonate, phosphate, and fluoride are
insoluble (Evans. 1990).
This document describes data for soluble lanthanum. The insoluble lanthanum salts are
expected to differ substantially from the soluble salts with respect to absorption, distribution, and
elimination, so are not the subject of this PPRTV assessment. Table 1 summarizes the
physicochemical properties of lanthanum and four of its commonly occurring soluble salts.
Lanthanum chloride (LaCb), CASRN 10099-58-8, is a white, transparent, hygroscopic,
crystalline solid that is soluble in water. It is produced by the treatment of lanthanum carbonates,
or oxides, with hydrochloric acid in an atmosphere of dry hydrogen chloride. Anhydrous
lanthanum chloride is often used to prepare the metal (Lewis and Hawlev. 2007). Data for
lanthanum chloride and its heptahydrate (LaCb*7H20), CASRN 10025-84-0, are shown in
Table 1.
Lanthanum nitrate hexahydrate [La(N03)3*6H20], CASRN 10277-43-7, is a white,
hygroscopic, crystalline solid that is soluble in water, alcohol, and acids. It is used as an
antiseptic and in gas mantles (Lewis and Hawlev. 2007). Data for lanthanum nitrate hexahydrate
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are shown in Table 1; no data on the physicochemical properties of anhydrous lanthanum nitrate
could be located.
Lanthanum acetate hydrate [La(CH3C00)3*H20], CASRN 100587-90-4, is a white
powder that is soluble in water and acid (Lewis and Hawlev. 2007). It is described as being
"somewhat less soluble" than the chlorides and nitrates (Bun/1 i. 2013). Data for lanthanum
acetate hydrate are shown in Table 1; no data on the physicochemical properties of anhydrous
lanthanum acetate could be located.
Soluble lanthanum salts, once dissolved in aqueous solution and biological systems,
would rapidly form La 3+ ions with bound water molecules. The solubility of La 3+ in aqueous
solution is pH dependent. At pH below -7.5, the La 3+ ion is bound to water molecules as its
soluble aqua ion [La(H20)83+], which would be the predominant lanthanum species found in the
stomach (pH 1-2). Above pH 7.5, as would be found in the small intestines and blood,
lanthanum will begin to precipitate out of solution as the bound water molecules are converted to
hydroxide ions [La(0H)3(H20)s]. In biological systems, La 3+ ions may also bind to other
oxygen donor molecules such as carboxylic acids (proteins) and phosphates (nucleic acids)
(Evans. 1990).
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Table 1. Physicochemical Properties of Lanthanum (CASRN 7439-91-0) and Soluble Salts3'b
Property (unit)
Lanthanum
Lanthanum Chloride,
Anhydrous
Lanthanum Chloride
Heptahydrate
Lanthanum Nitrate
Hexahydrate
Lanthanum Acetate
Hydrate
CASRN
7439-91-0
10099-58-8
10025-84-0
10277-43-7
100587-90-4
Formula
La
LaCl3
LaCl3-7H20
La(N03)3-6H20
La(CH3C00)3-H20
Physical state
Solid
Solid
Solid
Solid
Solid0
Boiling point (°C)
3,464
NA
NA
NA
NA
Melting point (°C)
920
858
91 (decomposes)
~40 (decomposes)
NV
Density (g/cm3 at 25°C)
6.15
3.84
NV
NV
NV
pH at which precipitation starts [0.1 M La(NO;,)3|
NA
NA
NA
NA
NA
Vapor pressure (mm Hg at 25 °C)
NA
NV
NV
NV
NV
Solubility in water (mg/L at 25 °C)
Insoluble
957,000
957,000
2,000,000
Soluble0
Atomic or formula weight (g/mol)
138.91
245.27
371.37
433.01
334.05
Flash point (°C)
NA
NV
NV
NV
NV
"Properties for lanthanum chloride hexahydrate, anhydrous lanthanum nitrate, and anhydrous lanthanum acetate were not available.
bHavnes (2014). unless otherwise specified.
"Lewis and Hawlev (2007).
La = lanthanum; La(CH3COO)3 = lanthanum acetate; LaCk = lanthanum chloride; La(NO;,)3 = lanthanum nitrate; NA = not applicable; NV = not available.
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A summary of available toxicity values for lanthanum and lanthanum compounds from
U.S. EPA and other agencies/organizations is provided in Table 2.
Table 2. Summary of Available Toxicity Values for Lanthanum (CASRN 7439-91-0)
and Lanthanum Compounds
Source (parameter)3'b
Value (applicability)
Notes
Reference(s)
Noncancer
IRIS
NV
NA
U.S. EPA (2018a)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012)
ATSDR
NV
NA
ATSDR (2018)
IPCS
NV
NA
IPCS (2018)
CalEPA
NV
NA
CalEPA (2016):
CalEPA (2018a):
CalEPA (2018b)
OSHA
NV
NA
OSHA (2017a):
OSHA (2017b)
NIOSH
NV
NA
NIOSH (2016)
ACGIH
NV
NA
ACGIH (2018)
DOE (PAC)
Lanthanum
PAC-1: 30 mg/m3;
PAC-2: 330 mg/m3;
PAC-3: 2,000 mg/m3
Based on TEELs
DOE (2016)
Lanthanum nitrate
hexahydrate
PAC-1: 1.3 mg/m3;
PAC-2: 15 mg/m3;
PAC-3: 89 mg/m3
Lanthanum chloride
PAC-1: 7.1 mg/m3;
PAC-2: 78 mg/m3;
PAC-3: 470 mg/m3
Lanthanum nitrate
PAC-1: 14 mg/m3;
PAC-2: 150 mg/m3;
PAC-3: 890 mg/m3
USAPHC (air-MEG)
Lanthanum
1-hr critical: 250 mg/m3;
1-hr marginal: 50 mg/m3;
1-hr negligible: 30 mg/m3
Based on TEELs
U.S. APHC (2013)
Lanthanum nitrate
hexahydrate
1-hr critical: 150 mg/m3;
1-hr marginal: 35 mg/m3;
1-hr negligible: 5 mg/m3
Lanthanum chloride
1-hr critical: 500 mg/m3;
1-hr marginal: 150 mg/m3;
1-hr negligible: 20 mg/m3
Cancer
IRIS
NV
NA
U.S. EPA (2018a)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012)
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Table 2. Summary of Available Toxicity Values for Lanthanum (CASRN 7439-91-0)
and Lanthanum Compounds
Source (parameter)3'b
Value (applicability)
Notes
Reference(s)
NTP
NV
NA
NTP (2016)
IARC
NV
NA
IARC (2018)
CalFPA
NV
NA
CalEPA (2011):
CalEPA (2018a):
CalEPA (2018b)
ACGIH
NV
NA
ACGIH (2018)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; CalEPA = California Environmental Protection Agency; DOE = U.S. Department
of Energy; DWSHA = Drinking Water Standards and Health Advisories; HEAST = Health Effects Assessment
Summary Tables; IARC = International Agency for Research on Cancer; IPCS = International Programme on
Chemical Safety; IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety
and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration;
USAPHC = U.S. Army Public Health Command.
Parameters: MEG = military exposure guideline; PAC = protective action criteria.
NA = not applicable; NV = not available; TEEL = temporary emergency exposure limit.
Non-date-limited literature searches were conducted in January 2016 and updated in
July 2018 for studies relevant to the derivation of provisional toxicity values for soluble
lanthanum and primarily focused on commonly occurring forms of the compound as follows:
lanthanum (CASRN 7439-91-0), lanthanum ion (La2+; CASRN 17643-88-8), lanthanum ion
(La3+; CASRN 16096-89-2), and soluble or moderately soluble lanthanum salts: lanthanide
nitrate (CASRN 35099-99-1), lanthanum acetate (CASRN 917-70-4), lanthanum bromide
(CASRN 13536-79-3), lanthanum chloride hexahydrate (CASRN 17272-45-6), lanthanum
chloride heptahydrate (CASRN 10025-84-0), lanthanum chloride (CASRN 10099-58-8),
lanthanum nitrate hexahydrate (CASRN 10277-43-7), lanthanum nitrate (CASRN 10099-59-9),
and lanthanum sulfate (CASRN 10099-60-2). Searches were conducted using U.S. EPA's
Health and Environmental Research Online (HERO) database of scientific literature. HERO
searches the following databases: PubMed, TOXLINE (including TSCATS1), and Web of
Science. The following databases were searched outside of HERO for health-related values:
American Conference of Governmental Industrial Hygienists (ACGIH), American Industrial
Hygiene Association (AIHA), Agency for Toxic Substances and Disease Registry (ATSDR),
California Environmental Protection Agency (CalEPA), European Centre for Ecotoxicology and
Toxicology of Chemicals (ECETOC), European Chemicals Agency (ECHA), International
Agency for Research in Cancer (IARC), Japan Existing Chemical Data Base (JECDB), National
Institute for Occupational Safety and Health (NIOSH), National Toxicology Program (NTP),
Organisation for Economic Co-operation and Development (OECD) High Production Volume
(HPV), OECD International Uniform Chemical Information Database (IUCLID), OECD
Screening Information Data Sets (SIDS), Occupational Safety and Health Administration
(OSHA), U.S. EPA Health Effects Assessment Summary Tables (HEAST), U.S. EPA HPV,
U.S. EPA Integrated Risk Information System (IRIS), U.S. EPA Office of Water (OW),
U.S. EPA TSCATS2/TSCATS8e, World Health Organization (WHO), Department of Energy
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(DOE) Protective Action Criteria (PAC), U.S. Army Public Health Command (APHC)
air-Military Exposure Guideline (air-MEG), and Defense Technical Information Center (DTIC).
Toxicity data were not located for lanthanum bromide or lanthanum sulfate; thus, these
compounds are not included in the "Introduction" section or considered further in this review.
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REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant noncancer and cancer databases,
respectively, for lanthanum and soluble salts, and include all potentially relevant repeated-dose
short-term-, subchronic-, and chronic-duration studies as well as reproductive and developmental
toxicity studies. Principal studies are identified in bold. The phrase "statistical significance,"
used throughout the document, indicates ap-value of < 0.05 unless otherwise specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Soluble Lanthanum (CASRN 7439-91-0)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Reported Doses,
Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
Short-term
10 (sex not specified);
Wistar rat; diet; 0, 75,
150 mg LaCly6H;0/kg:
18 d
0, 2.6, 5.17 mg La/kg-d
Significant increase in serum
ALP and ALT.
NDr
2.6
He et al. (2003)
PR: Liver weight
and
histopathology
were not
examined.
Short-term
10 M/10 F; Slc:Wistar rat;
gavage; 0, 40, 200,
1,000 mg LaCl3-7H20/kg-d;
daily for 28 d
0, 15, 74.8,
374 mg La/kg-d
Increased incidence of lung
lesions (granulation and giant
cell appearance) in males.
15
74.8
Oeawa (1992)
(Japanese with
English abstract
and tables)
PR
Subchronic
30 M/dose; ICR mouse;
gavage; 0, 2, 5,
10 mg LaCh/kg-d: daily for
90 d
0, 1, 3, 5.7 mg La/kg-d
Renal vein congestion and
serum chemistry changes
(increased creatinine; decreased
BUN and uric acid) were
reported.
NDr
NDr
Zhao et al. (2013)
PR: Due to poor
reporting and
unreliable
statistical results,
effect levels
could not be
identified.
Subchronic
10 M/10 F; S-D rat; gavage;
0, 1.5, 6.0, 24.0,
144.0 mg La(NC>3)3/kg-d;
daily for 90 d
0, 0.64, 2.6, 10.3,
61.6 mg La/kg-d
Significant decrease in body
weight in male rats, serum ALT,
AST in female rats.
10.3
61.6
Fang et al. (2018)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for Soluble Lanthanum (CASRN 7439-91-0)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Reported Doses,
Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Chronic
15 M/dose; Wistar rat;
gavage; 0, 0.1, 2,
40 mg LaCls/kg-d; 5 mo
(d/wk of treatment not
reported)
0, 0.06, 1,
23 mg La/kg-d
Significantly increased escape
latency in Morris water maze.
1
23
Feng et al.
(2006b)
PR: Only
neurotoxicity
endpoints were
examined.
Chronic
15 M/15 F; Wistar rat;
gavage; 0, 0.1, 0.2, 2.0, 10.0,
20.0 mg La(N03)3/kg-d;
6 d/wk for 6 mo
0, 0.036, 0.073, 0.73,
3.63, 7.26 mg La/kg-d
Hepatic lesions (turbulent
arrangements of hepatocyte
cords and infiltration of
inflammatory cells in the portal
area) and significant increase in
ALP. Decreased body-weight
gain was observed at
7.26 mg La/kg-d, but the
magnitude of change in absolute
body weight is not known.
3.63
7.26
Chen et al. (2003)
PR: Only liver
endpoints were
examined.
Chronic
10 M/dose; Wistar rat;
gavage; 0,
2.0 mg La(NC>3)3/kg-d; 6 mo
(d/wk of treatment not
reported)
0, 0.85 mg La/kg-d
Changes in bone composition
and mineral content indicative
of retarded bone maturation.
NDr
NDr
Huang et al.
(2006)
PR: Effect levels
were not
identified due to
the lack of
information on
biological
significance of
the observed
changes.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Soluble Lanthanum (CASRN 7439-91-0)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Reported Doses,
Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Developmental
(premating,
gestational, and
postnatal
exposure)
7-12 litters/dose;
Swiss-Webster mouse;
drinking water; parents
exposed to LaCl3'7H20 (0,
125, 250, 500 mg/L); from
14 d before mating through
mating, gestation, lactation,
until PND 60
Dams: ~0, 33.0, 66.1,
132 mg LaCl3'7H20/kg
-d (~0, 12.4, 24.7,
49.4 mg La/kg-d)
Pups: ~0, 41.9, 83.8,
168 mg LaCl3'7H20/kg
-d (~0, 15.7, 31.3,
62.7 mg La/kg-d)
Pup body weight decreased at
the mid and high dose.
Swimming behavior was
delayed at the mid and high
dose, but these results were
reported inconsistently in the
publication. At the low and mid
doses, but not the high dose,
delays in eye opening and ear
opening, as well as behavioral
alterations in the touch and
visual placing response tests
were observed.
NDr
15.7
(Pups)
NDr
31.3
(Pups)
Briner et al.
(2000)
(Water
consumption was
not measured.)
PR: Due to the
poor reporting
and uncertainty
regarding the
relationship of
the effects to
treatment, effect
levels were not
identified.
Developmental
(gestational and
postnatal
exposure)
8 litters/dose,
~4 M/4 F/litter; Wistar rat;
drinking water; LaCk at
concentrations of 0 or
0.25%; GD 7 to PND 21
Dams: 0,
407.1 mg LaCls/kg-d
(0, 230.6 mg La/kg-d)
Impaired olfactory function
(measured by buried food pellet
and olfaction maze tests) and
ultrastructural changes in the
olfactory epithelium (enlarged
olfactory receptor neuron knobs,
increased number of detached
knobs, decreased number of
cilia).
NDr
230.6
Hao et al. (2012)
(Water
consumption and
maternal body
weight were not
measured.)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for Soluble Lanthanum (CASRN 7439-91-0)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Reported Doses,
Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Developmental
(gestational and
postnatal
exposure)
8 litters/dose,
4-5 M/4-5 F/litter; Wistar
rat; offspring exposed to
LaCl3 in utero and via
lactation (parents via
drinking water at
concentrations of 0, 0.25,
0.5, or 1%); until PND 21
and then via drinking water
for 1 mo
Dams: 0, 407.1,814,
1,630 mg LaCls/kg-d
(0, 230.6, 461,
923 mg La/kg-d)
Pups: 0, 542.9, 1,090,
2,170 mg LaCh/kg-d
(0, 307.5, 615,
1,230 mg La/kg-d)
Impaired spatial learning and
memory (poor performance in
Morris water maze) and
ultrastructural changes in the
hippocampal synapses.
NDr
230.6
(Dam)
307.5
(Pup)
Zheng et al.
PR
(2013)
(Water
consumption and
maternal body
weight were not
measured.)
Developmental
(gestational and
postnatal
exposure)
~2-3 litters/dose; Wistar rat;
offspring exposed to LaCk
in utero and via lactation
(parents via drinking water
at concentrations of 0, 0.125,
0.25, 0.5, or 1%); until
PND 21 and then via
drinking water for 1 mo
Dams: 0, 544.9, 1,042,
1,990,
3,720 mg LaC^/kg-d
(0, 308.6, 590.0, 1,130,
2,100 mg La/kg-d)
Pups: 0, 619.0, 1,095,
2,000,
3,620 mg LaCh/kg-d
(0, 350.6, 620.3, 1,130,
2,050 mg La/kg-d)
Impaired spatial learning and
memory (poor performance in
Morris water maze).
NDr
308.6
(Dam)
350.6
(Pup)
Jin et al. (2017)
(Maternal body
weight was not
measured.)
PR
Developmental
(gestational and
postnatal
exposure)
8 litters/dose; Wistar rat;
offspring exposed to LaCk
via lactation (parents via
drinking water at
concentrations of 0, 0.125,
0.25, or 0.5%); until PND 21
and then via drinking water
for 2 mo
Dams: 0, 203.5,407.1,
814 mg LaC^/kg-d (0,
115.3,230.6,
461 mg La/kg-d)
Pups: 0, 271.4, 542.9,
1,090 mg LaCh/kg-d
(0, 153.7, 307.5,
615 mg La/kg-d)
Decreased body weight,
impaired spatial learning and
memory (poor performance in
Morris water maze), and
ultrastructural changes in the
hippocampal synapses.
NDr
115.3
(Dam)
153.7
(Pup)
Zhang et al.
PR
(2017)
(Water
consumption and
maternal body
weight were not
measured.)
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Table 3A. Summary of Potentially Relevant Noncancer Data for Soluble Lanthanum (CASRN 7439-91-0)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Reported Doses,
Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Developmental
(gestational and
postnatal
exposure)
10 litters/dose; Wistar rat;
offspring exposed to LaCk
in utero and via lactation
(parents via drinking water
at concentrations of 0, 0.125,
0.25, or 0.5%); until PND 21
and then via drinking water
for 1 mo
Dams: 0, 203.5,407.1,
814 mg LaC^/kg-d (0,
115.3,230.6,
461 mgLa/kg-d)
Pups: 0, 271.4, 542.9,
1,090 mg LaCh/kg-d
(0, 153.7, 307.5,
615 mg La/kg-d)
Impaired spatial learning and
memory (poor performance in
Morris water maze) and
ultrastructural changes in the
hippocampal synapses.
115.3
(Dam)
153.7
(Pup)
Zhang et al.
(2017)
(Water
consumption and
maternal body
weight were not
measured.)
PR
Developmental
(gestational and
postnatal
exposure)
15 dams/dose, 4 M/4 F/litter;
Wistar rat; offspring exposed
to 0, 0.1, 2, or
40 mg LaCls/kg-d during
gestation and lactation
(gavage administration to
dams) and via gavage from
PND 20 until 5 mo of age
0, 0.06, 1,
23 mg La/kg-d
Decreased body weight and
neurobehavioral changes
(decreased swimming endurance
and increased escape latency in
the Morris water maze).
1
23
Feng et al.
PR
(2006a)
Developmental
(gestational
and postnatal
exposure)
10 dams/dose, 5 M/litter;
Wistar rat; offspring
exposed to LaCb during
gestation and lactation
(gavage administration to
dams) and via gavage (0,
0.1,2, or
40 mg LaCb/kg-d) from
PND 21 until 6 mo of age
0, 0.06,1,
23 mg La/kg-d
Impaired performance in the
Morris water maze (increased
general path length, decreased
preference for target
quadrant) and decreased
numbers of pyramidal cells in
CA3 region of hippocampus.
0.06
1
He et al. (2008)
PR, PS
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Table 3A. Summary of Potentially Relevant Noncancer Data for Soluble Lanthanum (CASRN 7439-91-0)
Category3
Number of Male/Female,
Strain, Species, Study
Type, Reported Doses,
Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Developmental
(postnatal
exposure)
~4 M/4 F/litter,
8 litters/dose; Wistar rat;
offspring exposed to LaCk
via lactation (parents via
drinking water at
concentrations of 0, 0.25,
0.5, or 1%) until PND21
and then via drinking water
for 1 mo
Dams: 0, 407.1,814,
1,630 mg LaCls/kg-d
(0, 230.6, 461,
923 mg La/kg-d)
Pups: 0, 542.9, 1,090,
2,170 mg LaCh/kg-d
(0, 307.5, 615,
1,230 mg La/kg-d)
Impaired spatial learning and
memory (poor performance in
Morris water maze) and
ultrastructural changes in the
hippocampal synapses.
NDr
230.6
(Dam)
307.5
(Pup)
Yane et al. (2009)
(Water
consumption and
maternal body
weight were not
measured.)
PR
Developmental
(postnatal
exposure)
~4 M/4 F/litter,
8 litters/dose; Wistar rat;
offspring exposed to LaCk
via lactation (parents via
drinking water at
concentrations of 0, 0.25,
0.5, or 1%) from birth until
PND 21 and then via
drinking water for 1 mo
Dams: 0, 407.1,814,
1,630 mg LaC^/kg-d
(0, 230.6, 461,
923 mg La/kg-d)
Pups: 0, 542.9, 1,090,
2,170 mg LaC^/kg-d
(0, 307.5, 615,
1,230 mg La/kg-d)
Reduced levels of Nissl bodies
(a decrease indicates neural
degeneration) and ultrastructural
changes (chromatin
condensation and nuclear
fragmentation) in the
hippocampal neurons.
NDr
230.6
(Dam)
307.5
(Pup)
Yane et al. (2013)
(Water
consumption and
maternal body
weight were not
measured.)
PR
Developmental
(postnatal
exposure)
8/group; Wistar rat;
offspring exposed to LaCk
via lactation (parents via
drinking water at
concentrations of 0, 0.25,
0.5, or 1%) from birth until
PND 21 and then via
drinking water for 2 mo
Dams: 0, 407.1, 814, or
1,630 mg LaC^/kg-d
(0, 230.6, 461,
923 mg La/kg-d)
Pups: 0, 542.9, 1,090,
2,170 mg LaCl3/kg-d
(0, 307.5, 615,
1,230 mg La/kg-d)
Dose-related impairments of
spatial learning and memory
assessed by Morris water maze,
and alterations in morphology of
the hippocampal synapses.
NDr
230.6
(Dam)
307.5
(Pup)
Liu et al. (2014)
(Water
consumption and
maternal body
weight were not
measured.)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for Soluble Lanthanum (CASRN 7439-91-0)
Number of Male/Female,
Strain, Species, Study
Type, Reported Doses,
Reference
Category3
Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
(comments)
Notes0
2. Inhalation (mg/m3)
ND
aDuration categories are defined as follows: Acute = exposure for <24 hours; short term = repeated exposure for 24 hours to <30 days; long term (subchronic) = repeated
exposure for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002).
bDosimetry: Values are presented as ADDs (mg La/kg-day) for oral noncancer effects.
°Notes: PR = peer reviewed; PS = principal study.
ADD = adjusted daily dose; ALP = alkaline phosphatase; AST = aspartate aminotransferase; ALT = alanine aminotransferase; BUN = blood urea nitrogen;
F = female(s); GD = gestation day; La = lanthanum; LaCh = lanthanum(III) chloride; LaCl3'6H20 = lanthanum(III) chloride hexahydrate; LaCl3'7H20 = lanthanum(III)
chloride heptahydrate; La(NC>3)3 = lanthanum(III) nitrate; LOAEL = lowest-observed-adverse-effect level; M = male(s); ND = no data; NDr = not determined;
NOAEL = no-observed-adverse-effect level; PND = postnatal day; S-D = Sprague Dawley.
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Table 3B. Summary of Potentially Relevant Cancer Data for Soluble Lanthanum (CASRN 7439-91-0)
Category
Number of Male/Female, Strain, Species, Study
Type, Reported Doses, Study Duration
Dosimetry
Critical Effects
NOAEL
LOAEL
Reference
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
LOAEL = lowest-observed-adverse-effect level; ND = no data; NOAEL = no-observed-adverse-effect level.
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HUMAN STUDIES
The pulmonary toxicity of inhaled lanthanides, in general, has been the subject of debate,
especially regarding the relative contributions of radioactive contaminants versus stable elements
in the development of progressive pulmonary interstitial fibrosis (Beliles. 1994; Haley. 1991).
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 (Deng et aL 1991; Waring and Watling, 1990; Sulotto et ai, 1986; Yogt et aL 1986;
Colombo et al.. 1983; Vocaturo et aL, 1983; Sabbioni et aL. 1982; Husain et aL. 1980;
Kappenberger and Buhlmann. lA'"7?). Animal inhalation toxicity data on stable rare earths
consist of a few inhalation and intratracheal studies, on rare earth mixtures and some single
compounds (Abel a lbot. 1967; Mogilevskava and Raikfalin. 1967; Ball and Van Gelder.
1966; Schepers. 1955a. b; Schepers et al.. 1955). 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 indicative of pneumoconiosis and
progressive pulmonary fibrosis, and that the potential for inducing these lesions is related to
chemical type, physicochemical form, and dose and duration of exposure.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure to lanthanum chloride (or its hepta- or hexahydrate) were
investigated in an 18-day rat study (He et aL. 2003). a 4-week rat study published in Japanese
(Ogawa, 1992), a 3-month mouse study examining renal endpoints (Zhao et al., 2013), a 5-month
rat study examining neurotoxicity endpoints (Feng et aL. 2006b). and 11 developmental studies
examining neurotoxicity or olfactory effects, in rats or mice exposed during gestation, lactation,
and/or postnatally (Jin et al.. 2017; Zhang et al.. 2017; Liu et aL. 2014; Yang et al.. 2013; Zheng
et al.. 2013; Hao et al.. 2012; Yang et al.. 2009; He et al.. 2008; Feng et al.. 2006a; Bfiner et al..
2000). Gavage administration was used in five studies (Zhao et al.. 2013; He et al.. 2008; Feng
et al.. 2006a; Feng et al.. 2006b; Ogawa. 1992) and one study used dietary administration (He et
al.. 2003) while the remaining studies (Liu et al.. 2014; Yang et al., 2013; Zheng et al., 2013;
Hao et aL. 2012; Yang et al.. 2009; Briner et al.. 2000) used drinking water administration. The
effects of oral exposure to lanthanum nitrate were investigated in one 90-day gavage study (Fang
et al.. 2018). and two 6-month rat gavage studies examining liver (Chen et al.. 2003) and bone
(Huang et al.. 2006) endpoints.
Short-Term-Duration Studies
He et al (2003)
Groups of 10 Wistar rats (sex not specified) received dietary concentrations of 0, 75, or
150 mg lanthanum chloride hexahydrate (LaCb*6H20; purity 99%)/kg (0, 2.6, or
5.17 mg La/kg-day, calculated using body-weight and food-consumption data from the study) for
18 days (He et al.. 2003). Food intake was assessed daily, and body weight was measured every
3 days. At the end of exposure, blood samples were collected and analyzed for serum total
cholesterol, total protein, albumin, total triglycerides, glucose, creatinine, blood urea nitrogen
(BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP). At sacrifice, the thymus and spleen were weighed. Body weights did not
differ significantly from controls in either exposed group. At 5.17 mg La/kg-day, statistically
significantly increased ALP (57% higher than controls) and ALT (134% higher) were seen; there
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were no effects on other serum chemistry parameters, including BUN and creatinine
(see Table B-l). At 2.6 mg La/kg-day, a significant 82% increase in ALT was seen
(see Table B-l). A nonsignificant 20% increase in thymus weight was observed in high-dose
rats; spleen weight was not affected. A lowest-observed-adverse-effect level (LOAEL) of
2.6 mg La/kg-day is identified for these data based on a significant increase in serum ALT; note,
however, that liver weights and histopathology were not assessed, so the biological significance
of the serum chemistry changes is uncertain. A no-observed-adverse-effect level (NOAEL)
could not be identified.
Osawa (1992)
In a 28-day gavage study of lanthanum chloride in rats published in Japanese with an
English abstract and tables, lanthanum chloride heptahydrate (LaCb*7H20; purity 99.9%) was
administered by daily gavage to 10 Slc:Wistar rats/sex/dose. The vehicle used in this study was
potentially a 5% glucose solution based on a similar study conducted by this author (Ogawa,
1992). Doses were 0, 40, 200, or 1,000 mg LaCl3-7H20/kg-day (0, 15, 74.8, or
374 mg La/kg-day). A pair-fed control group was given the same diet intake as the high-dose
group. Additional control and high-dose groups of the same size were treated for 28 days, and
then observed untreated for an additional 14 days.
Evaluations were not detailed in the English abstract (Ogawa, 1992). Based on other
28-day studies of lanthanide elements by the same investigator (Ogawa et ai, 1995; Ogawa et
ai, 1992). and the tabulated and graphical results, investigations included observations for
mortality and clinical signs, measurement of body weights and food consumption, urinalysis,
hematology, serum chemistry, gross necropsy, selected organ weights, and comprehensive
histopathology on half of the animals per sex, per group. The study author measured lanthanum
and iron concentrations in the liver, kidney, and spleen, as well as in the bone. The study author
also measured the bone concentrations of barium, strontium, and zinc. Statistical assessments
were not described in the abstract or noted in the tables and figures.
Based on visual inspection of data presented graphically, body weights of the males
exposed to >74.8 mg La/kg-day were lower than untreated controls throughout the study,
reaching a decrease of—10% at the end of the treatment period that continued at the same
magnitude through the recovery period (Ogawa, 1992). There was no apparent effect on female
body weight. Similarly, food intake was decreased relative to untreated controls in the mid- and
high-dose males throughout the treatment period, but was not affected in females. Body weight
in the pair-fed controls mirrored that of the mid- and high-dose males. Hematology data reported
in graphs or tables were limited to eosinocyte ratios of the differential white blood cell (WBC)
count; these were significantly increased relative to untreated controls in males at all doses and
in females exposed to 74.8 mg La/kg-day (an increase in high-dose females was not statistically
significant due to substantial variability in individual values). Eosinocyte ratios in pair-fed
controls did not differ from untreated controls.
Serum chemistry and histopathology findings are reported in Tables B-2 and B-3.
Compared with untreated controls, the exposed animals exhibited significantly lower total
protein at the high dose; total protein was also decreased in the pair-fed controls (Ogawa, 1992).
In addition, high-dose rats of both sexes exhibited statistically significant increases in both ALT
and AST compared with both untreated and pair-fed controls. No statistically significant
changes in BUN or serum creatinine were observed in either sex when compared with untreated
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controls. At the high dose, BUN in both sexes and creatinine in females were increased relative
to pair-fed controls, but these values were lower than in untreated controls. Female rats
exhibited statistically significant and dose-related increases in serum uric acid relative to both
untreated and pair-fed controls; no significant changes were seen in males relative to either
control group. Female rats exhibited significantly lower serum cholinesterase at the mid and
high doses compared with untreated controls, and at the high dose when compared with pair-fed
controls. Organ-weight information was not reported in the abstract or English tables.
The study showed dose-related increases in tissue concentrations of lanthanum;
concentrations were highest in the liver (-2-5 |ig/g dry weight based on data shown graphically),
followed by kidney (<1 |ig/g), and bone and spleen (---<0.5 |ig/g) (Ogawa, 1992). Lanthanum
intake at the highest dose resulted in significantly decreased iron concentrations in the liver
(high-dose males and females), kidney (high-dose males), and spleen (high-dose females and
mid- and high-dose males). In addition, lanthanum exposure decreased the concentrations of
barium and strontium, while increasing zinc content in the bone. Histopathology findings were
reported for the lung and stomach; the report abstract stated that there were no findings in the
liver, and there were presumably no noteworthy findings in the kidneys or other organs.
Significantly increased incidences of granulation and giant cell appearance in the lung were
reported for males exposed to >74.8 mg La/kg-day and females exposed to 74.8 mg La/kg-day,
but not 374 mg La/kg-day (this lesion was seen in 1/5 high-dose females but the increase was not
significant; see Table B-3). High-dose females exhibited a significant increase in the incidence
of alveolar wall thickening, which could have obscured other lesions such as granulation and
giant cell appearance in this group. Eosinocyte infiltration was also observed in the lungs of
mid- and high-dose males and in mid-dose females, but not in the control animals or in the
control or dosed recovery groups. In addition, significantly increased incidences of lesions in the
forestomach, glandular stomach, and submucosa were observed in high-dose rats of both sexes
(see Table B-3): these included hyperkeratosis of the forestomach (females only), dilatation of
the acinus in the glandular stomach (males only), swelling of the glandular stomach epithelium
(females only), and eosinocyte infiltration of the submucosa (both sexes). Forestomach
hyperkeratosis and erosion of the glandular stomach were also seen in high-dose males, but the
incidences (2/5 and 3/5, respectively) were not statistically significantly increased over the
control incidence (0/5).
Based on the information provided in the English abstract, tables, and figures, a LOAEL
of 74.8 mg La/kg-day is identified based on increased incidences of pulmonary lesions
(granulation, giant cell appearance, and eosinocyte infiltration). The NOAEL is
15 mg La/kg-day.
Subchronic-Duration Studies
Zhao et al. (2013)
Lanthanum chloride (analytical grade, purity not reported) was administered in distilled
water by gavage to male ICR mice for 90 consecutive days in a study comparing renal effects of
lanthanum, cerium, and neodymium. The number of animals per group is uncertain; the study
authors reported n = 30/group, but also reported that 150 mice were randomly distributed among
10 groups (resulting in n= 15/group), and group sizes in the "Results" section of the study report
were given as n = 5/group. Doses were reported as 0, 2, 5, or 10 mg LaCb/kg-day (0, 1, 3, or
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5.7 mg La/kg-day).2 Mortality and clinical signs were noted daily, and body weight was
measured at the end of treatment. Blood collected at sacrifice was analyzed for serum markers
of kidney function (uric acid, BUN, creatinine, calcium, and phosphorus). No urine analyses
were performed. Kidneys were weighed and examined microscopically, and the lanthanum
content was analyzed. Markers of oxidative stress, antioxidant enzyme activity and gene
expression, and antioxidant levels in the kidney were measured. Statistical analyses consisted of
unpaired Student's ^-tests, without correction for multiple comparisons.
The study report presented no information on mortality or clinical signs. Significant,
dose-related decreases in body-weight gain were observed at all doses of lanthanum, but the
study authors did not report absolute body weights. Based on visual inspection of data presented
graphically, body-weight gains in treated mice were 10-30% lower than controls. Relative
kidney weights were increased in a dose-dependent fashion, likely due in large part to the
decreases in overall body-weight gain; the magnitude of change from control was also -10-30%
in the treated groups. Exposure to lanthanum chloride also resulted in a dose-related increase in
serum creatinine and dose-related decreases in serum uric acid, BUN, calcium, and phosphorus
(see Table B-4). The study authors reported that these changes were statistically significantly
different from controls at all doses. However, efforts to reproduce the statistical ^-tests using
data reported in the publication indicated that the changes in creatinine, BUN, calcium, and
phosphorus were not significant (p > 0.09) at the low dose, even without correction for multiple
comparisons, raising doubt about the reliability of the statistics reported in the publication. The
renal lesions, which consisted of congestion of the vein and mesenchyme blood vessel and
inflammatory cell infiltration, were reportedly observed at all doses of lanthanum chloride, but
neither the incidences nor severity of these lesions was reported. The study authors reported that
more serious renal lesions, including tubular necrosis, were seen in mice exposed to cerium and
neodymium. All markers of oxidative stress exhibited dose-related increases with lanthanum
treatment, along with accompanying decreases in antioxidant enzyme activities, protein levels,
and gene expression.
Data from this study suggest the possibility of lanthanum-induced effects on the kidney,
but the information provided is not sufficiently reliable to identify a NOAEL or LOAEL due to
poor reporting (neither incidence nor severity of renal lesions were reported) and unreliable
statistical results (some test results were demonstrably incorrect, and the overall approach failed
to account for multiple comparisons).
Zhao etal. (2013)
Lanthanum nitrate (La[NC>3]3; purity 98%) was administered once daily in distilled water
by gavage to 5-week-old Sprague-Dawley (S-D) rats (10/dose/sex) at dose levels of 0, 1.5. 6.0,
24.0, or 144.0 mg/kg-day (0, 0.64, 2.6, 10.3 or 61.6 mg La/kg-day) for 90 days. Five male and
five female rats from the highest dose group and control group (5/dose/sex) were observed in a
4-week recovery period. Mortality and clinical signs were noted daily, and body weight was
measured weekly during the treatment and at the end of treatment. Food consumption of each rat
was also measured weekly.
At the end of the study, urine samples were collected overnight and analyzed for
leukocytes, nitrite, urobilinogen, bilirubin, protein, glucose, specific gravity, pH, and occult
Corresponding lanthanum doses were calculated using the ratio of molecular weights (La:LaCl3 = 138.91:245.27).
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blood. Rats that fasted overnight were anesthetized, and blood was collected and subjected to
comprehensive hematological examination and serum biochemistry evaluation. All animals
received a complete necropsy, and the adrenals, brain, heart, kidneys, liver, spleen, thymus,
testes, and epididymis were weighted, and then subjected to histopathological examination.
Statistical analysis for differences between the treated and control groups used analysis of
variance (ANOVA) followed by Dunnett's test. Urinalysis and histopathological data were
analyzed using the Mann-Whitney U test.
The study authors reported no mortality or clinical signs at the end of study. Statistically
significant decreases in body weight (data were only reported in a graph) were observed in male
and female rats in the highest dose (61.6 mg La/kg-day) group, which were accompanied by
significant decreases in food intake. Based on a visual inspection of data presented graphically,
body weights of only male rats in the highest dose group decreased more than 10% compared to
the controls. In the male rats treated with 61.6 mg La/kg-day, the organ weights of the liver,
spleen, kidney, heart, and thymus were significantly decreased (see Table B-5), and the relative
brain and epididymis weights significantly increased compared to those in the controls. Most of
the hematological parameters were not significantly different between treated groups and the
control; however, significant differences were observed in some parameters, including an
increase in prothrombin time (PT) in male rats of the 0.64-mg La/kg-day dose group, and a
decrease in WBC and reticulocyte count (RET) in males of the 61.6-mg La/kg-day dose group.
There were dose-related decreases in blood triglyceride in males at dose levels
>10.3 mg La/kg-day. Exposure to 61.6 mg La/kg-day resulted in an increase in phosphorous in
male rats, and statistically significant increases in ALT, AST, glucose, urea, creatinine, and
calcium in female rats (see Table B-6). Urinalysis indicated no significant changes in any of the
nine urinary parameters between treated groups and controls (data not shown). Most of the
histopathological findings in all treated groups were comparable with those in the controls,
except of some observations in the heart, liver, kidneys, reproductive organs, and lungs, which
the study authors considered spontaneous background changes in S-D rats. Based on the
significant decreases in body weight in the male rats and increases in serum ALT and AST in
females, a LOAEL of 61.6 mg La/kg-day and aNOAEL 10.3 mg La/kg-day are identified.
Chronic-Duration Studies
Fengetol. (2006b)
A 5-month study of neurotoxicity endpoints was conducted in 4-week-old male Wistar
rats exposed to lanthanum chloride (purity 99.99%; vehicle not reported) (Feng et ai, 2006b).
Groups of 15 rats/dose received daily gavage doses of 0, 0.1, 2, or 40 mg LaCb/kg-day (0, 0.06,
1, or 23 mg La/kg-day). At 6 months of age, groups of 12 animals/dose were subjected to testing
for escape latency (no other metrics were assessed) in the Morris water maze every day for
8 consecutive days (four trials per day). Groups of three rats/dose were sacrificed after
behavioral testing, and their brains were examined by synchrotron radiation X-ray fluorescence
(SRXRF) analysis to map the distributions of calcium, iron, and zinc; additional brain samples
were analyzed for lanthanum using inductively coupled plasma-mass spectrometry (ICP-MS).
Additional groups of 10 rats/dose were sacrificed for measurement of monoamine
neurotransmitters and acetylcholinesterase (AChE) activity in the brain. Statistical analysis for
differences from control employed ANOVA followed by the least significant difference (LSD)
test.
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Rats exposed to 23 mg La/kg-day exhibited significantly increased escape latency in the
Morris water maze on Days 2, 3, and 4 of testing; no other statistically significant changes in
escape latency were observed (Feng et aL 2006b). Controls and low-dose animals learned the
maze within 3 or 4 days of testing, reaching an average escape latency of -20 seconds that
remained relatively constant through the remainder of testing, while high-dose rats took longer to
learn the maze, not reaching an average 20-second latency until Day 8 of testing. The rats in the
high-dose group also had lanthanum levels in the brain that were above detection limit; levels
ranged from 0.014 |ig/g dry weight in the hippocampus to 0.039 |ig/g in the cerebral cortex.
Lanthanum exposure, especially at the highest dose, decreased the concentrations of calcium,
iron, and zinc in the brain, and altered the distributions of these elements. In addition, the
activity of calcium-ATPase was significantly decreased in the brain at the high dose. Significant
decreases in several neurotransmitter levels (dopamine, dihydroxyphenylacetic acid,
5-hydroxytryptamine [5-HT], and norepinephrine) were observed at the high dose of lanthanum
chloride; 5-HT levels were also decreased at the mid dose (see Table B-7). However, the
functional significance of the change in 5-HT at the mid dose in and of itself is unclear. Levels
of the neurotransmitters, homovanillic acid and 5-hydroxyindoleacetic acid, were not
significantly altered by lanthanum treatment. Brain AChE activity was significantly decreased
and acetylcholine content increased at the low dose, but not at higher doses.
The delayed learning exhibited by rats exposed to lanthanum chloride may be related to
other changes, such as decreased calcium and zinc in the brain. Perturbations of neuronal
calcium homeostasis in the brain can have neurological effects, and decreased zinc in the
hippocampus (which is involved in spatial memory and navigation) is known to impair spatial
memory in rats (Feng et aL 2006b). Furthermore, decreases in neurotransmitter levels may also
be involved in memory impairment by lanthanum chloride. Several monoamine
neurotransmitters, including norepinephrine, dopamine, and 5-HT are reduced with age and/or
shown to impair working memory (Feng et aL, 2006b). Finally, decreased iron as seen in the
exposed rats may have led to the decreases in monoamine neurotransmitters, because iron is a
cofactor for many enzymes involved in the production of these neurotransmitters (Feng et aL
2006b).
Based on the significant delay in learning at the high dose and decreased multiple
neurotransmitter levels (dopamine, dihydroxyphenylacetic acid, 5-HT, and norepinephrine) at the
same dose, this study indicates a LOAEL of 23 mg La/kg-day for neurobehavioral effects; the
NOAEL is 1 mg La/kg-day.
Chen et al (2003)
Toxicity of lanthanum nitrate to the rat liver was evaluated in a 6-month study (Chen et
al.. 2003). Groups of Wistar rats (15/sex/dose) received lanthanum nitrate (purity 99.9%, in
physiological saline) at doses of 0, 0.1, 0.2, 2.0, 10.0, or 20.0 mg La(NC>3)3/kg-day (0, 0.036,
0.073, 0.73, 3.63, or 7.26 mg La/kg-day) by gavage 6 days/week for 6 months. At the end of
exposure, the animals were sacrificed and blood was collected for analysis of serum chemistry
(AST, ALT, y-glutamyl transferase [GGT], and ALP). Relative liver weight was measured, and
the liver was examined by light and transmission electron microscopy (TEM). Oxidative stress
indicators (superoxide dismutase [SOD], glutathione peroxidase, and malondialdehyde [MDA])
and lanthanum content in the liver were measured. Statistical analysis consisted of Student's
Mests.
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Body-weight gain was significantly lower than controls in male (but not female) rats
exposed to 7.26 mg La/kg-day (absolute body weight and body-weight gain data not shown). No
significant change in relative liver weight (and <10%) was observed in males exposed to
lanthanum nitrate (Chen et ai, 2003) (note that the study authors reported a significant increase
in relative liver weight in males exposed to 7.26 mg La/kg-day; however, efforts to reproduce the
statistical ^-tests using data reported in the publication indicated that the liver-weight changes in
male rats were not significant at any dose, calling into question the reliability of the statistics
reported in the publication). A significant decrease in relative liver weight was reported in
female rats exposed to 0.036 mg La/kg-day, but not other treatment groups. In male rats, but not
female rats, significant increases (confirmed by ^-tests performed for this review) in serum ALP
were noted at 0.036, 0.073, 0.73, and 7.26 (but not 3.63) mg La/kg-day, but there were no clear
dose-dependent changes at dose levels <3.63 mg La/kg-day; at the highest dose, serum ALP was
more than doubled (see Table B-8). No other serum chemistry changes were observed.
Oxidative stress markers were significantly increased at 0.036 and 0.073 mg La/kg-day, but not
higher doses, of lanthanum nitrate; the significance of this finding is uncertain. The lanthanum
content of the liver increased with dose. Lesions were observed in the livers of animals exposed
to 7.26 mg La/kg-day (the study authors did not specify which sex[es] were affected, and
incidences and severity were not reported) but not at lower doses or in controls; the lesions
consisted of "turbulent arrangements of hepatocyte cords" and infiltration of inflammatory cells
in the portal area. Glycogen depletion was also observed at the highest dose. TEM examination
of the hepatocytes showed numerous lysosomes containing electron-dense particles clustered
around bile canaliculi and perinuclear cytoplasm, as well as increased numbers of fat droplets,
especially at the highest dose. A LOAEL of 7.26 mg La/kg-day is identified for this study based
on hepatic lesions and a doubling of serum ALP. Decreased body-weight gain was also observed
at this dose, but the magnitude of change in absolute body weight is not known. The NOAEL is
3.63 mg La/kg-day.
Huane et al. (2006)
A study of lanthanum nitrate (purity not reported) effects on bone composition and
structure was conducted in male Wistar rats (10/dose) exposed by gavage for 6 months to doses
of 0 or 2.0 mg La(NO.OVkg-day (0 or 0.85 mg La/kg-day) (Huane et al.. 2006). Vehicle was not
reported. At sacrifice at the end of exposure, both femurs were removed for analysis of
lanthanum, calcium, and phosphorus content; bone mineral crystal size, orientation, thickness
and arrangement, calcium coordination in bone mineral, and bone mineral dissolution kinetics
were also examined. Data were analyzed by ANOVA and Scheffe's test.
Exposure to lanthanum resulted in statistically significant 11.6 and 16.7% decreases in
calcium and phosphorus content of the bone, respectively, a 10% decrease in the ratio of bone
mineral to matrix (relative to controls), and in the ratio of bone mineral to matrix (relative to
controls), as well as a significant 40.9% increase in carbonate content (see Table B-9) (Huane et
al.. 2006). Increased levels of labile carbonate and acidic phosphate were observed, and the
mean thickness of mineral crystals was decreased in the exposed rats. These changes make bone
mineral easier to dissolve, and studies of dissolution kinetics showed more rapid dissolution of
bone mineral from lanthanum nitrate-treated rats compared with controls. The study authors
considered these changes in bone composition and mineral content to be indicative of retarded
bone maturation (Huane et al.. 2006). However, in the absence of information on the functional
significance of altered bone composition and dissolution kinetics, the biological significance of
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this finding is uncertain and effect levels are not identified. Thus, neither a NOAEL nor a
LOAEL could be identified.
Developmental Studies
Briner et til. (2000)
A study of neurodevelopmental effects was conducted in Swiss-Webster mice exposed to
lanthanum chloride heptahydrate in drinking water (Briner et al.. 2000). Female mice were
exposed for 14 days before being mated to untreated males, and exposure continued through
mating, gestation, and lactation. After weaning, the pups were exposed to the same
concentrations as their mothers until sacrifice. Exposure concentrations were 0, 125, 250, or
500 mg LaCb*7H20/L. Water consumption was not measured, but based on default assumptions
for water intake and body weight, maternal doses of ~0, 33.0, 66.1, or
132 mg LaCb*7H20/kg-day (0, 12.4, 24.7, or 49.4 mg La/kg-day) were estimated, and pup doses
of -41.9, 83.8, or 168 mg LaCb*7H20/kg-day (0, 15.7, 31.3, or 62.7 mg La/kg-day) were
estimated. The pups were evaluated for eye and ear opening, as well as swimming ability every
day between Postnatal Days (PNDs) 4 and 20. Pup body weights were recorded on PNDs 4, 8,
12, 16, and 20. The pups were evaluated in a functional observational battery (FOB; excluding
the open field component, which the study authors reported was not affected in a pilot study)
between PNDs 30 and 32. At sacrifice on PNDs 59 or 60, the pups' brains were weighed and
analyzed for lanthanum, lipid, and protein content. Statistical analysis of continuous data
employed ANOVA with unspecified follow-up testing, and analysis of categorical data
employed the %2 test. The litter was the unit of statistical analysis.
The study authors stated that lanthanum chloride exposure did not affect maternal health
(evaluations were not reported) (Briner et al.. 2000). Litter size, sex ratio, and pup mortality did
not differ significantly between exposed and control mice; however, the study authors noted that
the litter size was slightly smaller at the high dose (7.6 ± 2.5 pups) compared with controls
(8.0 ± 3.3). Pups in the mid- and high-dose groups exhibited lower body-weight gain, although
body weights did not differ significantly from controls. Based on data presented graphically,
body weights of these two groups appeared to be >5% lower than controls on PND 20. The
percentage of pups with eyes open at PND 14 was significantly lower than controls at the low
and mid doses (-60 and -30%, respectively, compared with -80% in controls), but not at the
high dose (—90%); there were no differences at other time points for all doses. A similar
phenomenon was seen with the percentage of pups with ears open on PND 13 (-80, 44, 28, and
84%) in control, low-, mid-, and high-dose groups, respectively); the percentages did not differ at
other time points. None of the pups in the mid-dose group were walking by PNDs 5 or 6,
compared with ~65%> in the control and 25-50% in the other exposure groups; at later time
points, the groups did not differ. Results of assessments of swimming behavior were reported
inconsistently in the publication. In the graph presenting the results, the legend indicated that
significant delays in swimming behavior were seen in the low- and mid-dose groups, but not in
the high-dose group; in contrast, the text and the figure caption indicated that the significant
delays were seen in the mid- and high-dose groups. Thus, it appears likely that the figure legend
is in error, and that the swimming delays occurred at all but the lowest dose. In the FOB
assessment, only the touch response and visual placing response tests were altered by treatment
(Briner et al.. 2000). In both tests, the low- and mid-dose groups exhibited significantly different
behaviors compared with controls, while the high-dose group did not. A significant decrease in
absolute (but not relative) brain weight (data shown graphically) was observed in the high-dose
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pups. Brain levels of protein, lipids, and lanthanum did not differ significantly between the
exposed and control animals.
In summary, swimming behavior was delayed at the mid and high doses, although these
results were reported inconsistently. At the low and mid doses, but not the high dose, delays in
eye and ear opening were seen, as well as behavioral alterations in the touch and visual placing
response tests. However, the lack of effect at the highest dose raises uncertainty regarding the
relationship of these changes to treatment. The study authors suggested two possible
explanations for the lack of response at the high dose. The first was that lanthanum exposure
resulted in the death of embryos susceptible to lanthanum toxicity before birth. However, the
difference in litter size was not statistically significant (7.6 vs. 8.0). The second explanation,
based on in vitro studies showing that lanthanum can promote neurite formation, was that the
higher dose of lanthanum promoted pup growth, sped maturation, and resulted in developmental
milestones and behavior more resembling that of the controls. Because the study authors did not
measure water intake, it is also possible that the high-dose animals consumed less water than
other groups, potentially leading to a lower lanthanum dose than either of the other exposure
groups. It is also possible that the observed changes were not related to treatment. A LOAEL of
31.3 mg La/kg-day and NOAEL of 15.7 mg La/kg-day are identified based on the decreases in
body weight and delayed swimming behavior in pups.
Hao et al. (2012)
Groups of eight pregnant Wistar rats were exposed via drinking water to lanthanum
chloride (purity 99.9%) at a concentration of 0.25% from Gestation Day (GD) 7 to PND 21 (Hao
et al.. 2012). Water consumption was not measured. Based on default water intake and body
weight, the maternal doses were estimated to be approximately 0 and 407.1 mg LaCb/kg-day, or
0 and 230.6 mg La/kg-day (U.S. EPA, 1988). Maternal body weight, gestation length,
parturition success, litter size, and number of viable pups were recorded. The litters were culled
on PNDs 4 to 8/litter (4 males and 4 females when possible). Between PNDs 23-28, the pups
were tested for olfactory function in the buried food pellet and olfactory maze tests. In the
buried food pellet test, pups were placed on a food-restricted diet for 3 days before and during a
3-day testing period. During testing, the rats were placed in a cage containing a food pellet
under a 5-cm thickness of bedding material, and the time required for the rat to find the food
pellet was recorded. In the olfaction maze test, also conducted during the food-restricted period,
food was placed in a hidden location at a random corner in a maze to which the rats had become
familiarized, and the time between when the rat was placed at the center of the maze and when
the food was located was recorded. After olfactory testing was completed, the pups were
sacrificed for analysis of body, brain, and olfactory bulb weights, and the olfactory epithelia
were examined by TEM. Lanthanum content of the olfactory bulb was measured. Finally, the
olfactory epithelium was analyzed for protein and messenger ribonucleic acid (mRNA) levels of
olfactory marker protein and pill-tubulin, markers of olfactory maturation. Differences between
exposed and control measurements were analyzed by Student's t- and %2 tests; the unit of
statistical analysis was the litter.
There were no significant effects of treatment on gestation or litter parameters, or on pup
body, brain, or olfactory bulb weights (Hao et al.. 2012). The lanthanum content of the olfactory
bulb was significantly increased by exposure (18.5 vs. 2.3 ng/g in controls). In both olfactory
tests, a significantly increased latency for detection of food pellets was observed in exposed rats,
while latency to find a visible food pellet was not different between the exposed and control rats
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(see Table B-10). TEM examination of the olfactory epithelium confirmed treatment-related
effects consisting of enlarged olfactory reception neuron knobs, sometimes with irregular shapes,
significantly increased numbers of detached knobs, and significantly decreased numbers of cilia.
Exposure to lanthanum chloride also resulted in diminished expression of olfactory marker
protein and pill-tubulin. A LOAEL of 230.6 mg La/kg-day is identified from this study based
on impaired performance in olfactory testing and ultrastructural changes in the olfactory
epithelium at the only dose tested. A NOAEL could not be identified.
Zheng et al (2013)
In a similar study that included gestational exposure, pregnant Wistar rats (8/dose) were
given drinking water containing lanthanum chloride (purity 99.9%) at concentrations of 0, 0.25,
0.5, or 1% during pregnancy (details of exposure days not reported) and lactation (Zheng et al,
2013). Groups of 4-5 pups/sex/litter that were exposed during gestation and lactation were
subsequently exposed via drinking water at the same concentrations as their mothers for 1 month
postweaning. Water consumption and maternal body weight were not measured. The maternal
doses were estimated to be 407.1, 814, and 1,630 mg LaCb/kg-day, or 0, 230.6, 461, and
923 mg La/kg-day; the pup doses were estimated to be 542.9, 1,090, and 2,170 mg LaCb/kg-day,
or 0, 307.5, 615, 1,230 mg La/kg-day for pups.3 At the end of exposure, the pups were tested in
the Morris water maze. After testing, the pups were weighed and then sacrificed for
measurement of brain weight, quantification of lanthanum content in the hippocampus, and TEM
examination of the hippocampus. Hippocampal protein and mRNA levels of genes involved in
the NF-kB signaling pathway were measured. Data analysis consisted of ANOVA for
differences among groups followed by Student-Newman-Keuls (SNK) test for multiple
comparisons. The litter was the unit of statistical analysis for Morris water maze performance
metrics, as well as body and brain weights.
Zheng et al. (2013) and a series of similar studies conducted by the same research group
[including Jin et al. (2017); Zhang et al. (2017); Liu et al. (2014); Yang et al. (2013); Yang et al.
(2009)1 reported the exposure concentrations both as a percentage (without specifying
volume/volume [v/v] or weight/volume [w/v]) and as millimolar (mM) concentrations. Because
lanthanum chloride is a solid, it is assumed that the drinking water percentages were percent w/v,
or g/100 mL. Under this assumption, the concentrations reported as 0.25, 0.5, and 1% are
equivalent to concentrations of 2,500, 5,000, or 10,000 mg/L, respectively. The
mM concentrations (18, 36, and 72 mM) reported by the study authors correspond to these
concentrations only if the molecular weight of lanthanum (not lanthanum chloride) is used.
However, throughout the paper, the study authors refer to the concentrations as percent LaCb.
Thus, to calculate doses, the mM concentrations were ignored, and the percentages were
assumed to represent g/100 mL as LaCb.
Significant reductions in pup terminal body weights were observed at all the doses (6.7,
16.4, and 31.5% in low-, mid-, and high-dose groups, respectively; see Table B-1 1) (Zheng et al..
2013). Absolute, but not relative, brain weights were statistically significantly decreased in the
mid- and high-dose groups. Apart from brain and body weights, all results were presented
3Using a default estimate of body weight from subchronic-duration studies (0.156 kg) and water intake calculated
using an allometric equation (intake in L/day = 0.1 x [body weight in kg0-7377]), both from U.S. EPA (1988). the pup
doses from drinking water were estimated using a default estimate of body weight from studies of weanling animals
(0.0525 kg) and water intake was calculated using the same allometric equation.
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graphically. Statistically significant, dose-related impairments of spatial learning and memory
were evident from analysis of Morris water maze performance (increased escape latency and
total distance traveled, decreased time spent in target quadrant and number of target quadrant
crossings). Of these four metrics, the time spent in the target quadrant was significantly different
at the mid and high doses, while all others were significant at all doses. Dose-related alterations
in synaptic ultrastructure of the hippocampus, consisting of shorter synaptic active zones, thinner
postsynaptic density, fewer synaptic vesicles, and uneven curve of the synaptic interfaces, were
observed (quantitative results not reported). Treatment with lanthanum chloride also resulted in
dose-related reductions in the expression of phosphorylated IkB kinase complex, phosphorylated
IkBoi, NF-kB, c-fos, c-jun, and brain-derived neurotrophic factor (BDNF) in the hippocampus.
A LOAEL of 230.6 mg La/kg-day based on maternal exposure is identified from this study,
based on decreases in body weight, impaired spatial learning and memory (poor performance in
Morris water maze), and ultrastructural changes in the hippocampal synapses in pups. A
NOAEL could not be identified.
Jin el al. (2017)
In another study that included gestational exposure, pregnant Wistar rats (2-3/dose) were
given drinking water containing lanthanum chloride (purity 99.9%) at concentrations of 0, 0.125,
0.25, 0.5%, or 1% during pregnancy and lactation (3 weeks). The pups were exposed during
lactation, and subsequently exposed via drinking water at the same concentrations as their
mothers for 1 month postweaning. Because the study authors reported water consumption in
dams and pups, the doses were estimated based on the water consumption and default body
weight to be 0, 308.6, 590.0, 1,130, and 2,100 mg La/kg-day for dams and 0, 350.6, 620.3, 1,130,
and 2,050 mg La/kg-day for pups. At the end of exposure, 20 pups from each dose group were
tested in the Morris water maze. After testing, the pups were sacrificed for examination of the
hippocampus. Hippocampal protein and mRNA levels of glycogen synthetase, glycogen
phosphorylase, lactate dehydrogenase A, monocarboxylate transporter 4, MCT-1, and MCT-2, as
well as total lactate dehydrogenase (LDH) activity and lactate contents in the hippocampus were
measured. Data analysis consisted of an ANOVA for differences among groups followed by the
least significant difference test for multiple comparisons.
Statistically significant, dose-related impairments of spatial learning and memory were
evident from analysis of Morris water maze performance (increased escape latency and total
distance traveled, decreased time spent in target quadrant and number of target quadrant
crossings). All four metrics were significantly different from the controls at all doses.
Treatment significantly reduced the mRNA and protein levels of glycogen synthetase, glycogen
phosphorylase, lactate dehydrogenase A, monocarboxylate transporter 4, MCT-1, and MCT-2
and decreased the total LDH activity and lactate contents in the hippocampus. A LOAEL of
308.6 mg La/kg-day based on maternal exposure from drinking water is identified from this
study, based on decreases in impaired spatial learning and memory (poor performance in Morris
water maze) in pups. A NOAEL could not be identified.
Zhang et ol. (2017)
In a study that included only lactation exposure, maternal Wistar rats (8/dose) were given
drinking water containing lanthanum chloride (purity 99.9%) at concentrations of 0, 0.125, 0.25,
or 0.5% during lactation (3 weeks). Four pups (sex unknown) were culled in each litter. The
pups were exposed during lactation and subsequently exposed via drinking water at the same
concentrations as their mothers for 2 months postweaning. Water consumption and maternal
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body weight were not measured. The doses were estimated to be 0, 115.3, 230.6, and
461 mg La/kg-day for dams and 0, 153.7, 307.5, and 615 mg La/kg-day for pups. At the end of
exposure, 10 pups from each dose group were tested in the Morris water maze. After testing, the
pups were weighed and then sacrificed for measurement of brain weight and hippocampus
weight, pathological changes, and TEM examination of the hippocampus. Hippocampal protein
and mRNA levels of genes involved in the Nrf2/antioxidant response element signaling pathway
as well as reactive oxygen species indexes (reactive oxygen species [ROS], malondialdehyde
[MDA], glutathione [GSH], catalase, superoxide dismutase [SOD], and glutathione peroxidase
[GSH-Px]) were measured. Data analysis consisted of ANOVA for differences among groups
followed by SNK test for multiple comparisons.
Significant reductions in pup terminal body weights were observed at all the doses (10.6,
11.7, and 31.5% in low-, mid-, and high-dose groups, respectively; see Table B-12). Absolute,
but not relative, brain weights were statistically significantly decreased at all doses. There were
no statistically significant changes in absolute and relative hippocampus weight. Apart from
brain and body weights, all results were presented graphically. Statistically significant,
dose-related impairments of spatial learning and memory were evident from analysis of Morris
water maze performance (increased escape latency and total distance traveled, decreased time
spent in target quadrant and number of target quadrant crossings). Of these four metrics, escape
latency and number of target quadrant crossings were significantly different from the controls at
all doses, while time spent in the target quadrant and total distance traveled were significantly
different from controls at the mid and high doses. Treatment-related alterations in ultrastructure
of the CA1 and CA3 areas of the hippocampus, consisting of pyknosis of the cytoplasm and
nucleolus, swollen mitochondria and lysosomes, jagged edges of the nuclear envelope, and
increased number of endosomes in the lysosome, were observed (quantitative results not
reported). Treatment with lanthanum chloride also resulted in dose-related increases in ROS and
MDA content, as well as decreases in GSH, catalase, SOD, and GSH-Px in the hippocampi.
Significantly decreased Nrf2 mRNA and protein expression were observed in the hippocampi in
the mid- and high-dose groups. A LOAEL of 115.3 mg La/kg-day based on maternal exposure
from drinking water is identified from this study. Critical effects in pups included decreases in
body weight, impaired spatial learning and memory (poor performance in Morris water maze),
and ultrastructural changes in the hippocampal synapses. A NOAEL could not be identified.
Huetal. (2018)
In a study that included gestational exposure, pregnant Wistar rats (10/dose) were given
drinking water containing lanthanum chloride (purity 99.9%) at concentrations of 0, 0.125, 0.25,
or 0.5%) during lactation (3 weeks). The pups were exposed during lactation and subsequently
exposed via drinking water at the same concentrations as their mothers for 1 month postweaning.
Water consumption and maternal body weight were not measured. The doses were estimated to
be 0, 115.3, 230.6, and 461 mg La/kg-day for dams and 0, 153.7, 307.5, and 615 mg La/kg-day
for pups.
At the end of exposure, 6 pups from each dose group (1 pup/litter, 6/10 litters) were
examined for lanthanum content in the hippocampus. In addition, 6 pups from each dose group
(1 pup/litter, 6/10 litters) were tested in the Morris water maze. After Morris water maze testing,
the pups were randomly selected and the hippocampal tissue was collected for the following
experiments: TEM examination, extracellular glutamate and glutamine concentration analysis,
enzyme activity analysis (Na+-K+-ATPase, glutamine synthetase, phosphate-activated
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glutaminase), mRNA analyses (glutamate/aspartate transporter [GLAST], glutamate
transporter-1[GLT-1], N-methyl-D-aspartate receptor subunit GluNl, GluN2A and GluN2B),
protein analyses (glutamine synthetase [GS], phosphate-activated glutaminase [PAG], GLAST,
GLT-1, GluNl, GluN2A, and GluN2B) and immunofluorescence analysis (GluNl, GluN2A, and
GluN2B). An additional 6 pups from each dose group (1 pup/litter, 6/10 litters) were tested for
the electrophysiological analysis and intracellular [Ca2+] analysis. Data analysis consisted of
ANOVA for differences among groups followed by SNK test for multiple comparisons.
Lanthanum chloride treatment resulted in statistically significant and dose-dependent
increases in lanthanum content in the hippocampus. Statistically significant, dose-related
impairments of spatial learning and memory were evident from analysis of Morris water maze
performance during the training period (increased escape latency and total distance traveled) and
after 5 days resting (increased escape latency and total distance traveled, decreased time spent in
target quadrant and number of target quadrant crossings). Of these four metrics, time spent in
the target quadrant and number of target quadrant crossings were significantly different from the
controls at all doses, while escape latency and total distance traveled were significantly different
from controls at the mid and high doses.
Treatment-related alterations in ultrastructure of the CA1 areas of the hippocampus,
consisting of indistinct nuclear membranes, changed neuronal karyotheca, invisible cytoplasmic
organelles, swollen mitochondria, and nuclear fragmentation (quantitative results not reported).
Treatment with lanthanum chloride also resulted in dose-related increases in glutamate and
decreases in glutamine concentration in the hippocampi. Significantly decreased GLAST and
GLT-1 mRNA expression and protein expression were observed in the hippocampi in all treated
dose groups. There were also significant decreases in GS and PAG protein expression and
enzyme activity, and Na+-K+-ATPase activity in the hippocampi. The treatment resulted in
significant increases in mRNA and protein expression of GluNl, GluN2A, and GluN2B, which
was also confirmed by fluorescence intensity analysis and increases in intracellular [Ca2+],
Electrophysiological analysis indicated that after high-frequency stimulation, the population
spike amplitude of rats in the treated groups was significantly lower than in the control group. A
LOAEL of 115.3 mg La/kg-day based on maternal exposure from drinking water is identified
from this study based on impaired spatial learning and memory (poor performance in Morris
water maze), and ultrastructural changes in the hippocampal synapses. A NOAEL could not be
identified.
Fengetal. (2006a)
Groups of 15 pregnant Wistar rats received lanthanum chloride (purity not reported,
vehicle not reported) at daily gavage doses of 0, 0.1, 2, or 40 mg LaCb/kg-day (0, 0.06, 1, or
23 mg La/kg-day) throughout gestation and lactation (Feng et al.. 2006a). At birth, litters were
culled to four male and four female pups (when possible). After weaning at PND 20, the
offspring were exposed by gavage at the same doses as their mothers, until sacrifice. Pup body
weights were recorded at birth and on PNDs 30, 90, and 150. Neurobehavioral developmental
landmarks were recorded: pinna detachment was assessed on PND 2, eye opening was assessed
on PND 10, surface righting reflex was tested from PNDs 3-5, and swimming endurance was
tested on PNDs 12 and 20. Groups of 10 males randomly selected from each exposure level
were sacrificed at PND 30 for assessment of deoxyribonucleic acid (DNA) and protein levels in
the brain. Among the remaining pups, 12 males and 6 females randomly selected from each
group were tested in the Morris water maze at 5 months of age; four trials per day (with 6-minute
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rest periods between trials) were performed for 8 days, and mean latency time was recorded for
each day. Statistical analyses consisted of ANOVA followed by Student's Mest, using the
individual pup as the unit of analysis for the postweaning period and one male and one female
per litter for the preweaning period.
Litter size, pinna detachment, eye opening, and birth weight were not affected by
lanthanum chloride treatment (Feng et al.. 2006a). At the highest dose, pup body weights were
statistically significantly reduced (11.4 and 8.8% below controls for males and females,
respectively) at PND 150; statistically nonsignificant reductions of >5% were seen at this dose
on PND 90 (see Table B-13). At lower doses and other time points, there were no statistically or
biologically significant changes in body weight, apart from an 7.9% increase at 1 mg La/kg-day
on PND 90 that did not persist to PND 150. Surface righting reflex times in both sexes were
significantly shorter at doses >1 mg La/kg-day on PNDs 3 and 4, but not on PND 5; the
significance of this finding is uncertain given its lack of persistence. Swimming endurance time
was not affected by exposure on PND 12. Swimming endurance on PND 20, while significantly
increased at the 1 mg La/kg-day dose, was significantly decreased in both sexes compared to
controls at 23 mg La/kg-day, suggesting a toxicological effect at the highest dose. In the Morris
water maze testing of offspring at 5 months of age, exposure to the highest dose resulted in
significantly increased escape latency on Days 3, 4, and 5 of testing (data shown graphically); no
other significant differences were seen. Similar to results seen by Feng et al. (2006b). the
control, low-, and mid-dose animals appeared to learn the maze within 3-5 days, reaching a
relatively consistent escape latency of ±20 seconds, while high-dose animals learned more
slowly, achieving a 20-second latency by the 8th day of testing. Total DNA concentration in the
brain was significantly decreased at doses >1 mg La/kg-day, but the protein:DNA ratio did not
exhibit any treatment-related trends. A LOAEL of 23 mg La/kg-day is identified for this study
based on decreased pup body weight, decreased swimming endurance time, and increased escape
latency in the Morris water maze; the NOAEL is 1 mg La/kg-day. Changes in swimming
endurance time (increased) and surface righting reflex time (shortened) at 1 mg La/kg-day are
not judged to be toxicologically significant.
He et al (2008)
Groups of 10 pregnant Wistar rats were given lanthanum chloride (purity 99.9%, in
hydrochloric acid) by daily gavage from GD 0 through parturition and during lactation until
PND 20 (He et al.. 2008). Doses of 0, 0.1, 2, or 40 mg LaCb/kg-day were used (0, 0.06, 1, or
23 mg La/kg-day). At birth, litters were culled to 5 males/litter. At weaning, male pups were
exposed by gavage at the same doses as their mothers until 6 months of age. Once exposure was
concluded, the animals were weighed, and 15 randomly selected rats/group were tested in the
Morris water maze; the litter distribution of the selected animals was not reported. Testing
consisted of four 2-minute trials per day for 4 consecutive days, in which escape latency, general
pathway, and average swimming speed to find a submerged platform were measured. A trial for
memory consolidation was performed on the 5th day: the platform was removed and the
percentage of time spent in the target quadrant (target quadrant preference) was measured. The
final day of testing was to evaluate potential sensorimotor deficits by recording the rats' ability
to locate a visible platform. After testing, 7 rats/group were sacrificed for analysis of
intracellular free calcium, calcium-ATPase activity, and oxidative stress measures in the
hippocampus and cerebral cortex. An additional 4 rats/group from those tested in the water maze
were sacrificed for analysis of pyramidal cells in the CA1, CA3, and dentate gyrus (DG) areas of
the dorsal hippocampus (neurons were counted manually under light microscopy).
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Six rats/group among those not used for water maze testing, were sacrificed for analysis of
lanthanum concentration in serum, hippocampus, and cerebral cortex. Comparisons among
groups were done using ANOVA and Tukey's tests. Individual rats were the units of statistical
analysis.
Body weights of the pups were not affected by exposure to lanthanum chloride (He et al„
2008). All data, except for lanthanum content in the brain, were presented graphically. The data
for two measures of performance in the Morris water maze (length of pathway to platform and
preference for the target quadrant) and the numbers of pyramidal cells in the CA3 region of the
hippocampus were digitized from graphs in the publication using the Grablt! software and are
presented in Table B-14. Lanthanum concentrations in the serum, hippocampus, and cerebral
cortex of pups were significantly increased over controls at the highest dose. In water maze
testing, a significant impairment of spatial learning and memory was observed. While
swimming speed did not differ among the groups, escape latency was significantly increased at
the highest dose, and general pathway (total distance) was increased at the mid and high doses.
In the test for memory consolidation, preference for the target quadrant was significantly reduced
at doses >1 mg La/kg-day. In the CA3 region of the hippocampus, significantly lower numbers
of pyramidal cells (18-23% lower than controls) were observed at doses >1 mg La/kg-day; no
changes were observed in other regions of the hippocampus. Intracellular calcium in the
hippocampus was significantly increased, while calcium-ATPase activity was decreased, at the
highest dose of lanthanum chloride. Oxidative stress markers (increased MDA, decreased
catalase, SOD, and/or glutathione peroxidase) in the hippocampus and cerebral cortex were
significantly altered by exposure, primarily at the high dose. A LOAEL of 1 mg La/kg-day and a
NOAEL of 0.06 mg La/kg-day are identified for these data based on performance in the water
maze and decreased numbers of pyramidal cells.
Yansetal. (2009)
Yang et al. (2009) conducted a lactational and drinking water exposure study of
lanthanum chloride in Wistar rat pups. Lactating Wistar rats were given drinking water
containing lanthanum chloride (purity 99.9%) at concentrations of 0, 0.25, 0.5, or 1% for
3 weeks, exposing their pups (~4/sex/litter and 8 litters/dose) from birth to PND 21 by lactation.
Pups were then exposed directly via drinking water for 1 month at the same concentrations as the
dams. Water consumption and maternal body weight were not measured. The doses were
estimated as described previously for Zheng et al. (2013) to be approximately 0, 230.6, 461, and
923 mg La/kg-day for dams and 0, 307.5, 615, and 1,230 mg La/kg-day for pups. At the end of
exposure, the pups were trained in the Morris water maze for 5 days, rested for a week, and then
retested. Escape latency time was measured. After testing, the animals were sacrificed;
lanthanum content of the hippocampus was measured, and the hippocampal synaptic structure
(area CA1 only) was examined by TEM. Expressions of pCaMK IV, pMAPK, pPKA, pCREB,
c-fos, and egrl proteins in the hippocampus were evaluated by Western blotting and
densitometric analysis. Statistical comparisons among groups employed an ANOVA followed
by a SNK test. The litter was the unit of statistical analysis.
The lanthanum content of the hippocampus increased with dose to a maximum of
-0.055 |ig/g tissue (compared with <0.005 in controls) (Yang et al.. 2009). Dose-related
impairments of spatial learning and memory were evident from Morris water maze performance.
During training Days 2, 3, and 4, significant, dose-related increases in escape latencies were
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observed at all doses, indicating that the exposed rats had difficulty learning the maze. No
differences were seen on training Day 5 (see Table B-15). During retesting on Day 12 (after the
rest week), the exposed rats exhibited significantly longer escape latencies compared with their
Day 5 results and with controls, indicating impaired recall of the maze. The synaptic
ultrastructure of CA1 area in the hippocampus was significantly altered by exposure to
lanthanum chloride; changes in the exposed animals included fewer synaptic vesicles, short
active synaptic zone, uneven synaptic curvature, and thin postsynaptic density (quantitative data
not provided). Hippocampal expressions of pCaMK IV, pMAPK, pCREB, c-fos, and egrl
proteins were significantly reduced by treatment in a dose-dependent fashion. These data
indicate a LOAEL of 230.6 mg La/kg-day based on maternal exposure from drinking water (the
lowest dose tested) based on impaired spatial learning and memory (as tested in Morris water
maze), and ultrastructural changes in the hippocampal synapses of area CA1. A NOAEL could
not be identified.
Yansetal. (2013)
A subsequent study by the same laboratory used an identical exposure regimen [see Yang
et al. (2009)1. Water consumption and maternal body weight were not measured. The doses
were estimated as described previously for Zheng et al. (2013) to be approximately 0, 230.6, 461,
and 923 mg La/kg-day for dams, and 0, 307.5, 615, and 1,230 mg La/kg-day for pups. At the
end of exposure, the pups were sacrificed, and the hippocampi were removed for evaluation of
Nissl body levels (measured as integrated optical density in CA1, CA3, and DG areas), neuronal
ultrastructure (by TEM, CA1 area only), apoptosis, glutamate level, intracellular calcium level,
and endoplasmic reticulum (ER) stress markers. Statistical analyses employed an ANOVA
followed by a SNK test (for differences among groups). The litter was the unit of statistical
analysis.
All results were presented graphically in this study. A dose-related increase in the
concentration of lanthanum ion in the hippocampus (from -0.02 to -0.06 |ig/g tissue) was
observed in the treated rats (Yang et al.. 2013). Treatment with lanthanum chloride resulted in
dose-related decreases in the levels of Nissl bodies (indicative of neural degeneration) in the
CA1 and DG areas of the hippocampus that were significantly different from control at all doses,
and a decrease in Nissl body levels in the CA3 area that was significant at doses
>461 mg La/kg-day. In addition, alterations in the neuronal ultrastructure (chromatin
condensation and nuclear fragmentation) of the CA1 area of hippocampus were observed in
treated rats, but not in control rats (quantitative data not reported). Dose-related, statistically
significant increases in apoptosis, glutamate levels, and intracellular calcium levels were
measured in the hippocampi at all doses. The lowest dose in this study is identified as a LOAEL
of 230.6 mg La/kg-day based on maternal exposure from drinking water based on reduced levels
of Nissl bodies and ultrastructural changes in the hippocampal neurons. A NOAEL could not be
identified.
Liu et al (2014)
A third study by this laboratory (Liu et al.. 2014) extended the exposure duration by
1 month. Lactating Wistar rats were given drinking water containing lanthanum chloride
(purity 99.9%) at concentrations of 0, 0.25, 0.5, or 1% for 3 weeks, exposing their pups (number
reported only as eight/group) from birth to PND 21 by lactation. The pups were subsequently
exposed via drinking water at the same concentrations as their mothers for 2 months. Water
consumption was not measured. The doses were estimated to be 0, 230.6, 461, and
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923 mg La/kg-day for dams and 0, 307.5, 615, and 1,230 mg La/kg-day for pups. At the end of
exposure, the pups were tested for learning and memory in the Morris water maze. The rats were
first trained for 5 consecutive days to find a platform in the pool, and then rested for a week
before testing, during which escape latency, path length, and navigation path were measured.
One hour later, the platform was removed and the rats were allowed to swim for 60 seconds,
during which the number of target quadrant crossings, time spent and distance travelled in the
target quadrant, time from first entry to the target quadrant, and track plots were recorded.
Following testing, the pups were sacrificed, and the lanthanum contents of the hippocampi were
analyzed. Examination of the hippocampal synapses by TEM was performed. In addition,
analysis of the hippocampi for protein and mRNA levels of several genes involved in the
ERK/MSK1 signaling pathway was conducted. The data were analyzed using an ANOVA with
a post hoc SNK test. The litter was the unit of statistical analysis for the water maze
performance metrics; for hippocampal synaptic metrics, individual synapses were the unit of
analysis (50/group, litter distribution not reported).
All data were presented graphically. The concentration of lanthanum in the hippocampus
was increased with exposure from -0.025 |ig/g tissue at the low dose to -0.052 |ig/g tissue at the
high dose, demonstrating that lanthanum was absorbed from the drinking water and crossed the
blood-brain barrier (Liu et al.. 2014). Testing in the Morris water maze showed that exposure to
lanthanum chloride resulted in dose-related impairments of spatial learning and memory. During
the 5-day training period, dose-related increases in escape latency were observed on Days 3 and
4 (statistically significantly different from control at all doses on Day 3, and at the two higher
doses on Day 4). In addition, distance traveled was significantly longer at the high dose on
Day 3 and at the mid and high doses on Day 4. By Day 5, all groups performed similarly.
Dose-related increases in both escape latency (significant at all doses) and distance traveled
(significant at the mid and high doses) were also observed in the place navigation test after the
1-week rest period. Testing for spatial memory (with platform removed) showed dose-related
reductions (significant at all doses) in number of target quadrant crossings, time spent in the
target quadrant, and distance travelled in the target quadrant, as well as a significant, dose-related
increase in latency to first entry into the target quadrant. TEM examination of the hippocampus
showed dose-related effects on the synaptic interface structure that consisted of decreases in the
thickness of the postsynaptic density, length of the active zone, and synaptic curvature. These
changes were statistically significantly different from control at all doses (see Table B-16).
Lanthanum chloride exposure decreased the expression of several genes involved in the
ERK/MSK1 signaling pathway, including p-MEKl/2, p-ERKl/2, p-MSKl, p-CREB, c-FOS, and
BDNF. In this study, the lowest dose was associated with impairments in Morris water maze
performance (both learning and memory), as well as alterations in the morphology of the
hippocampal synapses; therefore, the low dose is a LOAEL of 230.6 mg La/kg-day based on
maternal exposure from drinking water (the lowest dose tested).
Inhalation Exposures
No studies of animals exposed to lanthanum or its soluble salts via inhalation have been
identified in the available literature.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Table 4A provides an overview of genotoxicity studies, and Table 4B provides an
overview of other supporting studies on lanthanum and soluble salts, including 1 acute oral
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lethality study, 1 short-term-duration (5 days) oral toxicity study, and 24 toxicity studies using
exposure routes other than oral or inhalation.
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Table 4A. Summary of Genotoxicity of Soluble Lanthanum
Endpoint
Test System
Doses/Concentrations
Tested
Results without
Activation3
Results with
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutagenicity
Salmonella typhimurium
strains TA97, TA98, TA100,
TA1535
0, 3.3, 10, 33, 100, 333,
1,000, 3,333,
10,000 ng/plate LaCk
Precipitate was present at >10 ng/plate.
Cytotoxicity was observed in TA97 at
10,000 ng/plate without S9 and >3,333 |ig/plate
with S9. A slight clearing of background lawn
was noted at >3,333 |ig/platc in TA98.
Zeiger et al.
(1992)
DNA adducts
Escherichia coli Q13
0, 100, 1,000 nM
La(CH3COO)3
+
+
Measured by 32P-postlabeling. La(CH3COO)3
induced DNA adducts in the presence and
absence of S9 activation or lysozyme or both.
Kubiiiskiet
al. (1981)
DNA repair
Bacillus subtilis strains H17
(Rec+, arg-, trp-) and M45
(Rec-, arg-, trp-)
0.00-0.5 M LaCl3 and
La(N03)3
NT
Using rec assay with cold incubation. Plates
were held at 4°C for 24 hr, then incubated
overnight at 37°C. La(NC>3)3 and LaCl3 were
highly toxic, but did not induce DNA damage.
Kanematsii
et al. (1980)
DNA repair
B. subtilis strains H17
(Rec+, arg-, trp-) and M45
(Rec-, arg-, trp-)
0.05 M LaCl3
NT
Using rec assay.
Nishioka
(19751
Genotoxicity studies in mammalian cells—in vitro
MN
Human peripheral
lymphocytes incubated with
La(N03)3-nH20 for 48 hr
0,0.016,0.04,0.1,0.25,
0.625 mM La
+
NT
La(N02,)vnH20 induced dose-related increase
in MN frequency at concentrations
>0.25 mM La. Cytotoxicity was observed, with
LC50 of 0.108 mM La in this system.
Yongxing et
al. (2000)
DNA strand
breaks
Human peripheral
lymphocytes incubated with
La(N03)3-nH20 for 1.5 hr
0, 0.004, 0.008, 0.016,
0.03 mM La
+
NT
Single cell gel electrophoresis (comet) assay.
La(N02,)vnH20 induced dose-related increase
in single strand DNA breaks at concentrations
of 0.04 mM La. Cytotoxicity was observed,
with LC50 of 0.108 mM La in this system.
Yongxing et
al. (2000)
Unscheduled
DNA
synthesis
Human peripheral
lymphocytes incubated with
La(N03)3-nH20 for 4.5 hr
0, 0.004, 0.008, 0.016,
0.03 mM La
+
NT
3H-TdR incorporation assay. La(N02,)ynH20
induced dose-related increase in unscheduled
DNA synthesis at concentrations of
0.04 mM La. Cytotoxicity was observed, with
LC50 of 0.108 mM La in this system.
Yongxing et
al. (2000)
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Table 4A. Summary of Genotoxicity of Soluble Lanthanum
Endpoint
Test System
Doses/Concentrations
Tested
Results without
Activation3
Results with
Activation3
Comments
References
Genotoxicity studies—in vivo
Bone marrow
mitotic index
Albino rats
(number/sex/group not
specified); LaCl3 was
administered i.p. every 24 hr
for up to 4 d (sacrificed at
24, 48, 72, or 96 hr), or as a
one-time dose with sacrifice
72, 96, or 110 hr later
Dose reported only as
one-fourth the LD50
NA
LaCL3 caused a decrease in the mitotic
frequency with repeated dosing; however, after
a >72-hr recovery, frequency was comparable
to controls.
Pe_and
Sharma
(1981)
CAs
Albino rats
(number/sex/group not
specified); LaCh was
administered i.p. every 24 hr
for up to 4 d (with sacrifice
at 24, 48, 72, or 96 hr), or as
a one-time dose with
sacrifice 72, 96, or 110 hr
later
Dose reported only as
one-fourth the LD50
±
NA
Total CAs were significantly increased 24 hr
after the initial dose, but did not increase
substantially with successive doses. After a
72-hr recovery, numbers of aberrations were
comparable to controls.
Pe_and
Sharma
(1981)
a+ = positive; ± = weakly positive; - = negative; NA = not applicable; NT = not tested.
CA = chromosomal aberration; DNA = deoxyribonucleic acid; i.p. = intraperitoneal; La = lanthanum; La(CH3COO)3 = lanthanum acetate; LaCk = lanthanum(III)
chloride; La(NC>3)3 = lanthanum(III) nitrate; La(N03)3-nH;0 = lanthanum nitrate hydrate; LC50 = median lethal concentration; LD50 = median lethal dose;
MN = micronuclei.
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Table 4B. Supporting Toxicity Studies
Test
Materials and Methods
Results
Conclusions
References
Acute/short-term oral exposure
Acute oral
lethality
Aqueous solutions of lanthanum chloride,
lanthanum nitrate, or lanthanum ammonium
nitrate were administered orally to S-D rats
(sex not specified) for determination of LD5o
values. The rats were observed for at least
10 d.
Details of time to death and clinical signs were not
reported. The study author reported that there were no
sex differences in lethality.
Oral LD5o values:
LaCl3 = 2,370 mg La/kg-d;
La(NC>3)3 = 1,450 mg La/kg-d;
La(N03)4NH4 = 830 mg La/kg-d
Dubois (1956);
Cochran et al.
(1950)
Short-term oral
toxicity
LaCl3 was administered to groups of 3 male
Wistar rats in drinking water at a dose
estimated by the study authors to be
0.77-0.9 mmol LaCh/kg-d (up to
-125 mg La/kg-d) for 5 d. At sacrifice at the
end of exposure, the ileum, liver, spleen,
kidney, lung, heart, brain, leg muscle, and
tongue muscle were weighed and examined
microscopically.
There were no effects of treatment on organ weights or
histopathology.
LaCl3 at an oral dose of
125 mg La/kg-d for 5 d did not
affect major organs of the rat.
Rabinowitz et
al. (1988)
Other route single exposure
Acute i.p.
lethality
La(NC>3)3 was administered i.p. to 35 female
CF1 mice; the animals were observed for
30 d.
For all the lanthanides tested, most mice died within
the first 8 d after dosing. Symptoms of toxicity were
not reported. Gross necropsy of randomly selected
survivors of all lanthanide exposure groups showed
generalized peritonitis with adhesions and
accumulation of ascitic fluid. Necropsy findings
specific to La were not reported.
Female mouse i.p.
LD5o = 131 mg La/kg
Bruce et al.
(1963)
Acute i.p.
lethality
LaCl3 was administered i.p. to CFW albino
mice (sex and number not specified) at doses
of 170 or 283 mg La/kg; the animals were
observed for 7 d.
33 and 77% of mice died at 170 and 283 mg La/kg,
respectively. Mean times to death were 32 and 37 hr,
respectively.
Mouse i.p. LD5o = 205 mg La/kg
Graca et al.
(1962)
Acute i.p.
lethality
LaCl3 was administered i.p. to guinea pigs
(strain, sex, and number not specified) at
doses of 28, 57, or 85 mg La/kg; the animals
were observed for 7 d.
5, 22, and 61% of guinea pigs died at 28, 57, and
85 mg La/kg, respectively. Mean times to death were
154, 54, and 45 hr, respectively.
Guinea pig i.p.
LD5o = 76 mg La/kg
Graca et al.
(1962)
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Table 4B. Supporting Toxicity Studies
Test
Materials and Methods
Results
Conclusions
References
Acute i.p.
lethality
Aqueous solutions of LaCh, La(NO;,)v or
La(N03)4NH4 were administered i.p. to S-D
rats (sex not specified) for determination of
LD5o. The rats were observed for at least
10 d.
Details of time to death and clinical signs were not
reported. The study author reported no sex differences
in lethality.
Rat i.p. LD50 values:
LaCl3 = 197 mg La/kg-d;
La(NC>3)3 = 145 mg La/kg-d;
La(N03)4NH4 = 153 mg La/kg-d
Dubois (1956)
Acute i.v.
toxicity
Male and female dogs (breed and sex not
specified, 3/group) received i.v. injections of
chlorides of 15 lanthanide elements.
Ten doses of 10 mg LaCh/kg (6 mg La/kg)
each were injected at 10-min intervals. Blood
samples were collected before treatment and
0, 10, 30, 60, 100, and 160 min after
treatment for analysis of erythrocyte,
leukocyte, and differential cell counts,
prothrombin and coagulation time,
hemoglobin, sedimentation, and Hct. After
160 min, the animals were necropsied and
tissues were collected for histopathology
(liver, spleen, kidney, lung, sternum,
mesentery lymph nodes, heart, adrenal, and
ovaries or testes). Heart rate, respiration, and
blood pressure readings were made at the
same intervals as blood samples.
Results for the 15 elements were discussed generally
and presented graphically. Some animals died from
treatment (14/45 treated with chlorides), but the
mortality was not reported by element. LaCh
treatment resulted in a steady decline in blood pressure
(down to about 60% of pretreatment values) and heart
rate (to about 70% of pretreatment values) over the
160-min observation period. Respiratory rates were
increased between 60-160 min postdosing. LaCk
resulted in increases in (to >100 sec by 60 min after
treatment) and coagulation time (to >60 min by 30 min
after treatment). Visual observation of pooled blood at
incision sites provided additional evidence of the
effect of lanthanide elements on clotting parameters,
but the incidence or specific treatment group(s) where
this was observed were not reported. Gross and
histopathological examinations revealed slight to
moderate hyperemia of the lungs.
i.v. exposure to LaCl3 impaired
clotting in dogs.
Graca et al.
(1964)
Acute i.v.
toxicity
Mixed breed rabbits (strain, sex, and ///group
not specified) received single i.v. doses of 0
or 20-100 mg LaCh/kg (10-60 mg La/kg) or
2-5 repeated doses of 10 mg LaCls/kg
(6 mg La/kg). Hemostasis parameters
(prothrombin activity, prothrombin
consumption, PTT, thrombin time,
fibrinogen, thromboelastogram, thrombocyte
count, thrombocyte factor 3, and
ADT-induced thrombocyte aggregation) were
evaluated (timing of evaluation not reported).
Results were not reported by dose. A single large dose
of LaCl3 (20-100 mg LaCh/kg) induced severe, acute
hemorrhagic diathesis in some animals, as well as
decreased PT and increased PTT. Repeated small
doses (2-3 doses of 10 mg LaC^/kg each) decreased
prothrombin consumption and increased fibrinogen
without affecting other parameters.
i.v. exposure to LaCl3 impaired
clotting in rabbits.
Naav et al.
(1976)
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Table 4B. Supporting Toxicity Studies
Test
Materials and Methods
Results
Conclusions
References
Acute i.v.
toxicity
Male ddY mice (3-6/group) were treated
with a single i.v. dose of 20 or
200 |imol La/kg (3 or 30 mg La/kg) as LaCk.
5 d after dosing, the animals were sacrificed
for assessment of testes weight and histology,
as well as lipid peroxidation and calcium
content in the testes.
Body weights were significantly lower than controls at
200 |imol La/kg but not at the low dose. Testes
weight, histology, and lipid peroxidation level were
not affected by exposure. The testicular calcium
concentration was significantly increased at both doses
of LaCl3.
i.v. exposure to LaCl3 increased
testicular calcium concentration
in mice.
Nagano et al.
(2000)
Acute
intratracheal
instillation
toxicity
Male Wistar rats (4/group) received a single
intratracheal instillation of LaCk at doses of
0, 0.5, 1, 10, 20, 50, 100, or 200 ng La/rat
and were sacrificed 2 d later. Lanthanum,
calcium, phosphorus, and sulfur were
measured in the lung, B ALF, femur,
pulmonary hilum lymph node, plasma, liver,
and kidney. BALF samples were analyzed.
A separate group of 4 rats was exposed to
50 |ig La/rat and sacrificed 1, 2, 3, or 14 d
later for light microscopy, TEM, and X-ray
microanalysis of the lung.
Histopathology of the lung showed increased numbers
of eosinophils. Alveolar macrophages of exposed rats
(50 |ig La/rat) exhibited many electron-dense granular
inclusions; electron-dense layers were seen on the
surface and in the basement membrane of Type 1
pneumocytes. Analysis of BALF 2 d after exposure
showed dose-related changes in LDH,
//-glucuronidase, protein, and sulfur, calcium, and
phosphorus content, as well as dose-related increases
in macrophage, PMN, and eosinophil counts. The
half-life for La in the lung was 244 d.
Intratracheal exposure to
50 |ig La/rat induced
histopathology changes in the
lungs and evidence for toxicity in
BALF.
Suzuki et al.
(1992)
Other route short-term toxicity
Short-term i.p.
toxicity in mice
Male CD-I (ICR) mice (15/group) received
daily i.p. injections of LaCk (0 or
20 mg LaCh/kg. equivalent to 0 or
11 mg La/kg-d) for 14 d. Animals were
examined daily for mortality and symptoms.
At sacrifice at the end of exposure, the mice
were weighed, and brains were weighed and
examined microscopically. Measures of
oxidative stress in the brain were analyzed.
Exposure did not affect survival, body-weight gain,
relative brain weight, or brain histology. No
significant effect was seen on O2- or H202-generating
rates, MDA content, or activities of SOD, catalase,
ascorbate peroxidase, or glutathione peroxidase in the
brain. Significant decreases in the ratios of
AsA:DAsA and GSH:GSSG, and in the total
antioxidant capacity of the brain were observed with
LaCl3 treatment. In addition, iNOS activity was
significantly decreased by exposure. Glutamate
content and AChE activity were significantly
increased by exposure to LaCl3.
i.p. exposure to 11 mg La/kg for
14 d did not affect brain weight
or histology in mice.
Zhao et al.
(2011)
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Table 4B. Supporting Toxicity Studies
Test
Materials and Methods
Results
Conclusions
References
Short-term i.p.
toxicity in mice
Male CD-I (ICR) mice (10/group) received
daily i.p. injections of LaCk (0 or
20 mg LaC^/kg, equivalent to 0 or
11 mg La/kg-d) for 14 d. Animals were
examined daily for mortality and symptoms.
Blood was collected for analysis of serum
chemistry. At sacrifice at the end of
exposure, the mice were weighed, and livers
were weighed and examined microscopically.
Expression levels of inflammatory cytokines
in the serum and liver were also measured.
Exposure did not affect survival, body-weight gain, or
relative liver weight. Serum ALT,
pseudocholinesterase, and total bilirubin were
significantly increased by exposure, while the ratio of
albumin:globulin, triglycerides, total cholesterol, and
both HDL- and LDL- cholesterol were decreased.
Mild histopathology changes in the liver consisted of
basophilia in a few hepatocytes and congestion of the
central vein. Significant increases in the expression of
inflammatory cytokines (NF-kB, MIF, IL-6, IL-ip,
CRP, TNF-a, IL-4, and IL-10) were observed in the
serum and liver.
i.p. exposure to 11 mg La/kg for
14 d induced mild liver lesions
and serum chemistry changes in
mice.
Fei et al.
(2011)
Short-term i.v.
toxicity in rats
White rats of both sexes (strain and numbers
not reported) received i.v. injection of
1.2 mg LaCls/kg-d (0.7 mg La/kg-d) for 2 or
4 d. At sacrifice, the liver was examined
microscopically and analyzed for enzyme
activity (nonspecific esterase, acid
phosphatase, phosphorylase, LDH, MDH,
and SDH).
No details of general animal health were reported.
Exposure to LaCl3 for 2 or 4 d resulted in decreases in
esterase, phosphorylase, SDH, LDH, and MDH
activities; statistical analysis of the changes was not
reported. Histopathological changes in the livers of
exposed animals were described as "diffuse cellular
lesions" after 2 d of exposure and "specific
necrobiosis" after 4 d.
i.v. injection of 0.7 mg La/kg-d
for 2 or 4 d resulted in liver
lesions in rats.
Kadas et al.
(1973)
Short-term i.v.
toxicity in rats
Groups of 4 white rats of both sexes (strain
not reported) received i.v. injection of
1.2 mg LaCh/animal-d (0.7 mg La/animal-d)
for 2 or 4 d, or a single dose of
15 mg LaCls/animal (8 mg La/animal). At
sacrifice 1 or 24 hr after dosing, the liver was
examined by light and electron microscopy.
No details of general animal health were reported.
Light microscopy revealed changes corresponding to
those described in Kadas et al. (1973).
Ultrastructurally, the "diffuse cellular lesions"
consisted of enlarged nucleoli, irregularly shaped
aggregates of glycogen granules or scarce glycogen
granules, and focal areas of vesicular transformation of
rough ER. Electron-dense granules were seen in the
bile canaliculi. The "specific necrobiosis" changes
were seen on electron microscopy as swollen
centrilobular cells, decreased rough ER and increased
vesicular-type ER, increased numbers of mitochondria
with decreased electron density and partially destroyed
cristae, and swollen biliary epithelium.
i.v. injection of 0.7 mg La/kg-d
for 2 or 4 d resulted in liver
lesions in rats.
Kadas et al.
(1974)
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Table 4B. Supporting Toxicity Studies
Test
Materials and Methods
Results
Conclusions
References
Short-term i.v.
toxicity in
rabbits
Male rabbits (strain not reported, total n = 28)
received single or repeated i.v. injections of
29-310 mg LaCl3 (16-176 mg La) for
1-28 d. A control group of 2 rabbits was
untreated. At sacrifice, the liver, spleen,
kidney, heart, lungs, GI tract, pancreas, bone
marrow, adrenal gland, and testes were
examined for gross and microscopic
pathology.
Gross findings included hyperemia in the lungs and
pale livers in exposed animals. Among rabbits
exposed for acute durations (up to 1 d), the primary
microscopic finding was characterized as "diffuse
cellular lesions" in the liver. With prolonged exposure
or higher doses, histopathology findings included the
diffuse lesions as well as "specific necrobiosis."
i.v. injection of LaCl3 resulted in
lung hyperemia and hepatic
lesions.
Kadas and
Jobst (1973)
Short-term
intranasal
instillation
toxicity in mice
Male CD-I (ICR) mice (15/group) received
daily intranasal instillations of LaCh (0 or
20 mg LaCh/kg. equivalent to 0 or
11 mg La/kg-d) for 14 d. Animals were
examined daily for mortality and symptoms.
At sacrifice at the end of exposure, the mice
were weighed, and lungs were weighed.
Measures of oxidative stress in the lung were
analyzed.
Exposure did not affect survival, body-weight gain, or
relative lung weight. No effect on O2, H2O2, or NO
production rates was seen. A significant increase in
lung MDA content was observed, and SOD, total
antioxidant capacity, and ratio of GSH:GSSG in the
lung were significantly decreased.
Intranasal instillation of
11 mg La/kg-d increased
oxidative stress measures in the
lung in mice without affecting
lung weight.
Li et al. (2010)
Other route chronic toxicity
Chronic i.v.
toxicity in rats
Male rats (strain not reported, total n = 103)
received single or repeated i.v. injections of
0.6-30 mg LaCb (0.3-17 mg La) for 1-95 d.
A control group of 5 rats was untreated. At
sacrifice, the liver, spleen, kidney, heart,
lungs, GI tract, pancreas, bone marrow,
adrenal gland, and testes were examined for
gross and microscopic pathology.
Gross findings included hyperemia in the lungs and
livers of exposed animals. Among rats exposed for
acute durations (up to 1 d), the primary microscopic
finding was characterized as "diffuse cellular lesions"
in the liver. With prolonged exposure or higher doses,
histopathology findings included the diffuse lesions as
well as "specific necrobiosis."
Chronic i.v. exposure to LaCl3
resulted in lung hyperemia and
hepatic lesions.
Kadas and
Jobst (1973)
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Table 4B. Supporting Toxicity Studies
Test
Materials and Methods
Results
Conclusions
References
Chronic
intranasal
instillation
toxicity in mice
Male CD-I (ICR) mice (30/group) received
nasal instillation of LaCk daily for 6 mo at
doses of 0, 2, 5, or 10 mg LaCh/kg-d (0, 1, 3,
or 6 mg La/kg-d). Toxicological evaluations
included mortality, signs of toxicity, body
weight, BALF analysis, and lung weight and
histology. Oxidative stress markers in the
lung were measured.
A dose-related decline in body-weight gain was
observed, with statistically significant changes at all
doses. Lung weight relative to body weight was
increased at >3 mg La/kg-d. Significant increases in
macrophages, lymphocytes, neutrophils, eosinophils,
LDH, ALP, and total protein were observed in BALF
at all exposure levels. Lung histopathology changes in
exposed mice included abscission or fragmentation of
epithelial cells, edema, infiltration of inflammatory
cells, and thickening of pulmonary interstitium at all
exposures. Oxidative stress markers were
significantly increased at all exposures.
Intranasal instillation of LaCl3 at
1 mg La/kg-d for 6 mo resulted
in decreased body weight and
lung lesions.
Hone et al.
(2015)
Other route developmental toxicity
Developmental
toxicity after
i.p. exposure of
mice
Pregnant ICR Swiss albino mice (11-28)
received a single i.p. injection of 44 mg La/kg
on GDs 4, 6, 8, 10, 12, 14, or 16. Controls
received deionized water on GDs 14 or 16.
Fraction of females continuing pregnancy and
average litter size were recorded. In a
separate experiment, groups of 16 pregnant
mice were exposed on GD 4 and implantation
sites were recorded at sacrifice on GD 5.
The fraction of females continuing pregnancy was
significantly decreased from control in groups exposed
to LaCl3 on GDs 4, 6, 14, and 16. In addition, average
litter size per continuing pregnancy was significantly
decreased in groups exposed on GDs 4, 12, 14, and 16.
Exposure on GD 4 significantly decreased the
numbers of females with at least one implantation site
and the average number of implantation sites per
pregnant female on GD 5.
i.p. exposure of mice to LaCl3
impaired pregnancy maintenance,
decreased litter size, and
decreased implantations.
Abramczuk
(1985)
Other route neurotoxicity
Neurotoxicity
after i.p.
exposure of
rats
Male albino Wistar rats (7/group) received
daily i.p. injections of LaCl3'7H20
(53 mg LaCl3'7H20/kg or 20 mg La/kg) for
7 consecutive d. One hr after the last dose,
the rats were sacrificed. Total antioxidant
status and activities of AChE,
Na+/K+-ATPase, and Mg2+-ATPase activities
in the brain were determined.
The study authors reported that there were no
behavioral or physiological effects of treatment (no
details of evaluations provided). Exposure resulted in
a significant decrease (36% relative to controls) in
brain total antioxidant status. Na+/K+-ATPase activity
was significantly decreased (28%), as was
Mg2+-ATPase activity (8%). A significant increase in
AChE activity in the brain (23%) occurred in treated
rats. Cotreatment with cysteine partially mitigated the
effects on total antioxidant status and AChE activity
but not the effects on ATPase activity.
i.p. exposure of rats to
LaCk-7H20 increased AChE
activity in the brain and
decreased total antioxidant status
in the brain.
Liaoi et al.
(2009)
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Table 4B. Supporting Toxicity Studies
Test
Materials and Methods
Results
Conclusions
References
Neurotoxicity
after s.c.
exposure of
rats
Pregnant Long-Evans rats received a single
dose of 175 mg LaCh/kg (100 mg La/kg) by
s.c. injection on GD 10 and dams were
allowed to deliver. Pups were weighed daily
from PNDs 4-14. Between PNDs 18-22, the
pups were tested every other day for
swimming behavior. Swim ability was
scored between 0 (unable to get nose out of
water) to 3 (able to get nose and more than
half of head out of water).
Pup weights were not affected by exposure.
Swimming scores were lower than controls in exposed
rats on PNDs 8, 10, 14, and 18, but by PND 22, all
pups were scored similarly.
s.c. exposure to LaCk in utero
temporarily delayed swimming
behavior in rats.
Wadkins et al.
(1998)
Neurotoxicity
after
intracerebro-
ventricular
injection in rats
Male Wistar rats (5/group) received
lanthanum (0, 0.1, 1.0, or 10.0 mM LaCl3 or
0, 0.06, 0.6, or 6 mM La) by
intracerebroventricular injection, followed by
1.p. injection of cocaine (0 or 10 mg/kg).
Motor activity was recorded at 15-min
intervals after exposure.
Exposure to lanthanum did not affect motor activity in
rats not exposed to cocaine. In rats exposed to
cocaine, La treatment at concentrations >0.6 mM
prevented the increase in motor activity induced by
cocaine.
Intracerebroventricular exposure
to LaCl3 inhibited
cocaine-induced motor activity in
rats.
Kiizmin and
Zwartau_Q996}
Neurotoxicity
after
intracranial
injection in rats
S-D rats (number and sex not specified)
received microinjections of LaCk (83 or
47 |ig La) in the brain. Antinociceptive
response was measured by tail flick and hot
plate tests at intervals between 15-120 min
after exposure.
Exposure to LaCk inhibited responses in the tail flick
and hot plate tests 30 and 60 min after exposure, but
not 120 min after exposure. Coexposure to CaCCb
blocked the effect of LaCk
Intracranial exposure to LaCl3
induced an analgesic effect in
rats.
Harris et al.
(1975)
Neurotoxicity
after
intracranial
injection in
chicks
Lohmann brown domestic chicks (8/group)
received a single intracranial injection of
lanthanum chloride (0, 1, 5, or 10 mM, or 0,
0.6, 3, or 6 mM La) 1 wk after hatching. The
chicks were weighed every 2 d for 7 d. The
chicks were observed for locomotor activity
2 d after exposure, and tested for detour
learning (ability of animal to reach goal when
an obstacle is placed between subject and
goal; considered a functional test for CNS
development) daily from 3-7 d postexposure.
LaCl3 exposure did not affect body weight or
horizontal locomotion. Significant delays in response
latency were seen in the tests of detour learning among
chicks exposed to >3 mM La.
Intracranial injection of LaCl3
impaired detour learning in
chicks.
Che et al.
(2011)
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Table 4B. Supporting Toxicity Studies
Test
Materials and Methods
Results
Conclusions
References
Neurotoxicity
in chicks after
injection in
embryonic
eggs
Fertilized chick eggs (46/group) were injected
with lanthanum chloride (0, 0.1, 2, or
40 mg LaCls/kg, or 0, 0.06, 1, or
20 mg La/kg) on embryonic D 9-16. 1 d
after hatching, the chicks were tested in a
one-trial passive avoidance learning task
(avoidance of pecking a bead with a bad
flavor) as a measure of long-term memory.
After sacrifice at the end of testing, La
content in the intermediate medial
mesopallium and medial striatum portions of
the brain was measured.
There were no effects on egg weight, hatch day, or
hatch weight; however, hatch rate declined with dose
from 85% for saline-injected eggs to only 6.5% for
eggs exposed to 20 mg La/kg. Because the number of
chicks was so low in the group exposed to
20 mg La/kg, neurobehavioral testing was not
conducted in this group. Significantly decreased mean
avoidance rate was observed in chicks after exposure
to 1 mg La/kg, but not at the low dose. Significantly
increased La concentrations in the brain were noted at
both 0.06 and 1 mg La/kg.
Injection of LaCl3 into chick eggs
resulted in impaired long-term
memory in chicks.
Che et al.
(2009)
Neurotoxicity
after
intracranial
injection in
chickens
Day-old black Australorp x white Leghorn
chickens (16/group) received intracranial
injection of LaCl3-7H;0 (5 mM or 2 mM La)
immediately after a visual reminder for the
passive learning avoidance test they had
previously mastered. The chicks were
retested at various time points after the
reminder.
Exposure resulted in transient loss of memory on
retesting, only when the test material was administered
after a visual reminder. The deficit remained when
testing occurred up to 40 min after the reminder; in
later testing (60 and 180 min after the reminder), there
was no difference from control.
Intracranial exposure to LaCl3
inhibited immediate memory
recall in chicks.
Summers et al.
(1996)
AChE = acetylcholinesterase; ADT = androgen deprivation therapy; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AsA = L-ascorbate;
BALF = bronchoalveolar lavage fluid; CaCCb = calcium carbonate; CNS = central nervous system; DAsA = dehydroascorbate; ER = endoplasmic reticulum;
GD = gestation day; GI = gastrointestinal; GSH = glutathione; GSSG = oxidized glutathione; H2O2 = hydrogen peroxide; Hct = hematocrit; HDL = high-density
lipoprotein; iNOS = inducible nitric oxide synthase; i.p. = intraperitoneal; i.v. = intravenous; K = potassium; La = lanthanum; LaCh = lanthanum(III) chloride;
LaCl3'7H20 = lanthanum(III) chloride heptahydrate; La(NCh)3 = lanthanum(III) nitrate; La(N03)4NH4 = lanthanum ammonium nitrate; LD50 = median lethal dose;
LDH = lactate dehydrogenase; LDL = low-density lipoprotein; MDA = malondialdehyde; MDH = malate dehydrogenase; Mg = magnesium; Na = sodium; NO = nitrogen
oxide; O2 = oxygen; PMN = polymorphonuclear leukocyte; PND = postnatal day; PT = prothrombin time; PTT = partial thromboplastin time; s.c. = subcutaneous;
S-D = Sprague-Dawley; SDH = succinic dehydrogenase; SOD = superoxide dismutase; TEM = transmission electron microscopy.
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Genotoxicity
Lanthanum chloride yielded negative results when tested in vitro for mutagenicity in
Salmonella (Zeiuer et a I.. 1992) and for DNA repair in Bacillus subtilis using the rec assay
(Kanematsu et al. 1980; Nishioka, 1975). In an in vivo rat test, intraperitoneal (i.p.)
administration of lanthanum chloride at a dose reported only as one-fourth the median lethal dose
(LD50) did not increase the bone marrow mitotic frequency, but did induce a transient increase in
the chromosome aberration (CA) (Pe and Sharma. 1981). A single study (Kubinski et aL 1981)
in Escherichia coli showed increased DNA adduct formation with exposure to lanthanum
acetate; no other studies of this compound were located. Lanthanum nitrate induced increased
frequencies of MN and DNA strand breaks, and unscheduled DNA synthesis in human
peripheral lymphocytes tested in vitro without metabolic activation (Yongxing et al.. 2000). but
did not increase DNA repair in B. subtilis in a rec assay with cold incubation (Kanematsu et al,
1980). In summary, the mutagenicity and genotoxicity data for soluble lanthanum salts are
limited, but available data suggest that lanthanum nitrate may be genotoxic in human
lymphocytes.
Acute and Short-Term-Duration Oral Studies
Oral LD50 values of 2,370, 1,450, and 830 mg La/kg were reported for lanthanum
chloride, lanthanum nitrate, and lanthanum ammonium nitrate, respectively, in S-D rats (Dubois.
1956; Cochran et al.. 1950). A 5-day exposure of male Wistar rats to 125 mg La/kg-day in
drinking water did not result in effects on organ weights or histopathology changes in major
organs (Rabinowitz et al.. 1988).
Other Route Toxicity Studies
Intraperitoneal lethality studies suggest low oral absorption of soluble lanthanum
compounds; i.p. rat LD50 estimates were between one-fifth and one-twelfth of corresponding oral
values (197, 145, and 153 mg La/kg for lanthanum chloride, lanthanum nitrate, and lanthanum
ammonium nitrate, respectively, when administered i.p., compared with 2,370, 1,450, and
830 mg La/kg when administered orally) (Dubois. 1956). Lethality data, while limited, provide
some evidence for species differences in susceptibility to i.p.-administered LaCb; the guinea pig
LD511 was 76 mg La/kg, compared with 205 mg La/kg for mice in the same study (Graca et al..
1962). This also is supported by mice LD50 reported by Bruce et al. (1963).
Studies of acute exposure to LaCb administered intravenously demonstrate that this
compound impairs clotting parameters in dogs and rabbits (Nagy et al.. 1976; Graca et al.. 1964).
Nagano et al. (2000) reported increased testicular calcium concentrations in mice given a single
i.v. dose of LaCb, but no effects on testes weight or histology were seen. No other studies
examining potential male reproductive effects of soluble lanthanum salts were located.
Liver lesions were observed in several studies of rats, mice, and rabbits exposed to LaCb
by i.p. or i.v. injection (Fei et al.. 2011; Kadas et al.. 1974; Kadas et al.. 1973; Kadas and Jobst,
1973). In mice, the lesions consisted of hepatocyte basophilia and central vein congestion (Fei et
al.. 2011). In rats and rabbits, the effects were described as "diffuse cellular lesions" or "specific
necrobiosis" (Kadas et al.. 1974; Kadas et al.. 1973; Kadas and Jobst. 1973). Using electron
microscopy, Kadas et al. (1974) further characterized the diffuse cellular lesions as enlarged
nucleoli, irregularly shaped aggregates of glycogen granules or scarce glycogen granules, and
focal areas of vesicular transformation of rough ER; the "specific necrobiosis" changes were
seen on electron microscopy as swollen centrilobular cells, decreased rough ER and increased
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vesicular-type ER, increased numbers of mitochondria with decreased electron density and
partially destroyed cristae, and swollen biliary epithelium.
A study of intratracheal instillation showed signs of toxicity in bronchoalveolar lavage
fluid (BALF) and an inflammatory response (increased eosinophils) in the lungs of rats exposed
to LaCb at a dose of 50 |ig La/rat (Suzuki et al.. 1992). After intranasal instillation of LaCb at a
dose of 1 mg La/kg for 6 months, lung lesions were observed in exposed mice, along with
increased markers of oxidative stress in the lung (Hone et al.. 2015). A shorter duration of
exposure (14 days at 11 mg La/kg-day) by this route also resulted in evidence for oxidative stress
in the lungs (increased lipid peroxidation) (Li et al.. 2010).
Developmental toxicity was observed in mice exposed by i.p. injection to 44 mg La/kg
(as LaCb) on a single day during gestation (Abramc/uk. 1985). Exposure on GDs 4, 14, or 16
decreased the fraction of females continuing pregnancy and the average litter size. Exposure on
GD 6 decreased the fraction of females continuing pregnancy without affecting litter size, while
exposure on GD 12 decreased litter size without affecting pregnancy continuation. Finally,
exposure on GD 4 also decreased the number of females with at least one implantation site and
the average number of implantation sites per pregnant female on GD 5 (Abramc/uk. 1985).
The potential neurotoxicity of LaCb has been examined in rats and chickens exposed by
injection routes. In rats, i.p. exposure to LaCb increased brain AChE activity and increased
oxidative stress in the brain (Liapi et al.. 2009). After subcutaneous (s.c.) injection of LaCb to
dams during pregnancy, rat pups exhibited a temporary delay in swimming behavior that was no
longer evident by PND 22 (Wadkins et al.. 1998). Intracranial injection of LaCb in rats inhibited
responses in tail flick and hot plate tests (Harris et al.. 1975). and inhibited the increase in motor
activity induced by i.p. injection of cocaine (Kuzroin and Zwartau. 1996). Neurobehavioral
effects (decreased mean avoidance rate in passive avoidance learning task, delays in response
latency in tests of detour learning, or transient memory loss) were seen in chickens exposed by
injection into embryonic eggs (Che et al.. 2009) or intracranial injection (Che et al.. 2011;
Summers et al.. 1996).
Mode-of-Action/Mechanistic Studies
Target organs or systems identified in oral toxicity studies of soluble lanthanum salts
include the nervous system (including olfaction), liver, kidney, bone, and lung (see Table 3A).
Based on the identified LOAELs in Table 3A, the most sensitive organ or systems are the
nervous system, kidney, and bone. In the single study identifying renal effects of LaCb (Zhao et
al.. 2013). oxidative stress was increased in the kidney at doses that also induced kidney lesions,
suggesting that induction of oxidative stress may be involved in the mechanism of kidney
toxicity. No other information on mechanisms of kidney toxicity were located.
The effects of lanthanum on bone composition may relate to the element's similarity to
calcium in ionic radius and/or its ability to sequester phosphate via formation of insoluble
lanthanum phosphate (Huang et al.. 2006). In addition to being similar in ionic radius to calcium
(and thus able to substitute for calcium in bone), lanthanum is known to block calcium channels
that may be involved in critical signaling during bone remodeling (Huang et al.. 2006). In vitro
studies have shown that exposure to LaCb can affect osteoblast and osteoclast proliferation,
differentiation, and/or mineralization (Jiang et al.. 2016; Liu et al.. 2012; Wang et al.. 2008;
Zhang et al.. 2007).
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Lanthanum's effects on the central nervous system (CNS) may also stem from its ability
to interfere with calcium homeostasis. Zarros et al. (2013) reviewed mechanistic data and
outlined plausible mechanistic pathways for lanthanum-induced effects on cognitive function and
the hippocampus. As described by these study authors, effects on spatial learning and memory
are initiated by translocation of lanthanum into hippocampal cells via calcium gateways, leading
to displacement of intracellular calcium from its binding sites. Calcium displacement generates
mitochondrial dysfunction and oxidative stress, leading to the cells' failure to maintain long-term
potentiation (believed to play a role in long-term storage of spatial and contextual memories) and
triggering apoptosis. Lanthanum may also exert neurotoxic effects by interfering with the
calcium-calmodulin complex, leading to decreased activation of Ca2+ calmodulin-dependent
protein kinases that regulate transcription and translation in Nissl bodies of genes, necessary for
synaptic consolidation and long-term potentiation (Zarros et al.. 2013). Other studies (Jin et al..
2017; Zhang et al.. 2017) also suggested that perturbation of the Nrf2-antioxidant response
element signaling pathway or suppression of astrocyte-neuron lactate shuttle may also be
responsible for the impaired spatial learning and memory of rats.
Metabolism/Toxicokinetic Studies
The oral absorption of lanthanum and other lanthanide elements is very low, in part
because these elements form insoluble hydroxides at neutral pH. While an estimate of the
gastrointestinal (GI) absorption of lanthanum itself is not available, studies of other lanthanides
in a wide variety of species suggested fractional absorption estimates in the range of 10 6 to 10 3
for all of the lanthanides [reviewed by Leggett et al. (2014)1. Little is known about the
absorption of inhaled lanthanides. Leggett et al. (2014) noted that the ionic solutions of
lanthanides are not stable at neutral pH, often forming colloidal or hydroxide complexes; such
behavior may result in wide variations in lung clearance rates.
The lanthanide elements are typically deposited in the bone, liver, and kidney, although
deposition varies with route of exposure. Leggett et al. (2014) reported median molar
concentrations of lanthanum and other lanthanides in a number of tissues based on data obtained
by Zhu et al. (2010) as cited in Leggett et al. (2014) from 68 adult males in China. The nature,
magnitude, and routes of lanthanide exposures in this population were not described by Leggett
et al. (2014). The highest lanthanum concentrations were in the lung (448 nmol/kg fresh
weight), liver (248 nmol/kg), and rib (194 nmol/kg), followed by stomach (109 nmol/kg), small
intestine (103 nmol/kg), thyroid (94 nmol/kg), and heart (86 nmol/kg). Other tissues and blood
had lower concentrations. Leggett et al. (2014) indicated that the data were very uncertain due to
potential errors in measuring low concentrations and high variability in the measured
concentrations. Distribution of lanthanum after oral exposure was reported in a study of male
Wistar rats exposed to lanthanum chloride in drinking water (Rabinowitz et al.. 1988). After
1 day of exposure to 140LaCb at a dose estimated by the study authors as
0.77-0.9 mmol LaCb/kg-day (-100-125 mg La/kg-day), the highest tissue concentrations of
radioactivity were in the intestine, lung, kidney, liver, and tongue muscle (see Table 5). In rats
exposed for 2 or 3 days, concentrations of 140La in soft tissues remained fairly constant, while
concentrations in the bone and teeth increased. The study authors suggested that the soft tissues
quickly reached a dynamic equilibrium, while bone and teeth continued to absorb lanthanum.
Using acid washes of the teeth, the investigators demonstrated that the highest lanthanum
concentration was in the surface of the teeth; 50% of the lanthanum in teeth was removed by
four acid washes that dissolved only 1% of the tooth weight. This finding suggests that
lanthanum was deposited on the teeth during intake of the drinking water, rather than through
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systemic distribution. Rabinowitz et al. (1988) also evaluated the fractional distribution of140La
in the liver of exposed rats. After either 1 or 2 days of exposure, most of the radioactivity was
found in the soluble fraction of the liver (62-68% of liver radioactivity), with lesser amounts in
the membranes (21-26%), mitochondria (99—10%), and nuclei (-2%).
Table 5. Tissue Distribution of 140La after Administration of LaCb in Drinking Water to
Male Wistar Rats"'b
Tissue
Concentration of 140La (nmol La/g Tissue) after 1,2, or 3 d of Exposure
1 d
2d
3 d
Ileum
36 ±30
38 ±5
29 ±4
Lung
35 ± 10
24 ±6
33 ±8
Kidney
24 ±8
27 ±3
23 ±2
Liver
23 ±7
18 ±8
23 ±8
Spleen
13 ±2
15 ±3
12 ± 1
Femur bone
13 ±5
16 ±5
27 ±5
Incisor tooth
12 ±4
24 ±3
55 ±6
Tongue muscle
22 ±3
25 ±4
29 ±5
Heart muscle
8 ± 4
12 ±4
6 ± 2
Leg muscle
7 ± 3
9 ± 3
8 ± 2
Brain
2 ± 1
1 ± 1
1± 1
aRabinowitz et al. (1988).
bMean± SEM.
La = lanthanum; LaCk = lanthanum (III) chloride; SEM = standard error of the mean.
Toxicity studies that evaluated the distribution of lanthanum after oral exposure of rats to
lanthanum chloride showed dose-related increases in tissue concentrations of lanthanum after
both gavage (Feng et al, 2006b; Qgawa, 1992) and drinking water exposure (Liu et al. 2014;
Yang et al, 2013; Hao et al.. 2012; Yang et al, 2009). In a 28-day study that measured
lanthanum in several tissues (Qgawa, 1992). concentrations were highest in the liver (-2-5 |ig/g
dry weight based on data shown graphically), followed by kidney (<1 jug/g), and bone and spleen
(~<0.5 |ig/g). Neurodevelopmental studies provided evidence that lanthanum crossed the
blood-brain barrier; levels up to -0.06 ng/g have been measured in the hippocampus (Liu et al.
2014; Yang et al. 2013; Yang et al. 2009; Feng et al. 2006b). In addition, one study (Hao et al.
2012) demonstrated deposition of lanthanum in the olfactory bulb (18.5 ng/g compared with
2.3 ng/g in controls).
Male S-D rats (10/group) received a single intragastric dose of 10 mg LaCb.
Two rats/group were sacrificed 1 hour, 6 hours, 24 hours, 2 days, or 3 days after dosing for
examination of the distribution of lanthanum in the intestinal barrier (Floren et al.. 2001).
Results were described generally for several soluble lanthanide compounds similarly tested.
Submicroscopic precipitates, primarily in the apical portion of the duodenum, were seen up to
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2 days after dosing. After 3 days, no precipitate was seen. These data demonstrate that soluble
lanthanide compounds precipitate in the proximal part of the intestinal tract.
Cuddihv and Boecker (1970) examined the kinetics of140La elimination after gavage,
inhalation, and i.v. injection exposure of male and female beagle dogs to lanthanum chloride.
After a single gavage dose of 25 mg 140La, whole-body radioactivity declined rapidly during the
first 2 days (to -0.1% of the initial body burden) and more slowly for the remaining 6 days of
observation (to -0.015% of initial body burden). In contrast, after i.v. (0.25 mg 140La) exposure,
whole-body radioactivity declined slowly but steadily over the 8-day observation to —2—5% of
initial body burden. Data on inhalation exposure were from an experiment in which the dogs
were exposed to a mixture of 140LaCb and cesium chloride; the kinetics of elimination were like
that seen with i.v. injection exposure. After inhalation exposure to the mixture, the highest
concentrations of 140La were found in the nasal turbinates, followed by lung, GI tract, liver,
bones, and bronchial lymph nodes.
After i.v. exposure to 0.03 mg/kg-day lanthanum chloride in rats for 28 consecutive days,
the liver, femur, kidney, and heart had concentrations of 2,593, 1,627, 231, and 96 ng/g tissue,
respectively (Damment et ai, 2009). The concentration of lanthanum in the skin was reported to
be <160 ng/g; in the brain, the concentration was close to the limit of quantitation (-2-11 ng/g).
Long-term retention of lanthanum has not been studied; however, Durbin et al. (1956)
measured retention of cerium (a lanthanide close to lanthanum in the series) in the skeleton over
256 days, and observed a two-phased elimination curve. The study authors reported that about
one-third of the skeletal cerium was labile, with a half-life of about 15 days, while the remaining
two-thirds was retained at the same level throughout the remaining 8 months. If lanthanum
behaves similarly, a portion of skeletal lanthanum will be rapidly eliminated while the remainder
persists unchanged.
No data were found on the excretion of soluble lanthanum salts after exposure of humans
or animals. After oral administration of other lanthanide elements (yttrium, dysprosium,
europium, and ytterbium, as their chloride hexahydrates) to male Wistar rats, none of these
elements was detected in urine, and 92-98% of administered doses (100 and
1,000 mg lanthanide elements/kg) was excreted in the feces within 7 days [Nakamura et al.
(1991); published in Japanese with English abstract and tables]. Excretion of orally administered
lanthanum chloride is likely to follow a similar pattern. In rats exposed intravenously to
lanthanum chloride (0.3 mg/kg), the majority of the administered dose (74%) was excreted in the
feces over 42 days, and <2% was excreted in urine (Damment and Pennick. 2007). In an
experiment using bile duct-cannulated rats exposed to the same dose, 10% of the administered
dose was excreted in bile over the 5 days during which bile was collected (Damment and
Pennick. 2007).
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DERIVATION OF PROVISIONAL VALUES
There are no data to derive reference values for lanthanum metal. Tables 6 and 7 present
summaries of noncancer and cancer references values, respectively, for soluble lanthanum
compounds.
Table 6. Summary of Noncancer Reference Values for Soluble Lanthanum
Toxicity Type
(units)
Species/
Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal
Study
Subchronic p-RfD
(mg La/kg-d)
Rat/M
Decreased number of pyramidal
cells in hippocampus
5 x 1(T5
BMDL
0.016
300
He et al,
(2008)
Chronic p-RfD
(mg La/kg-d)
Rat/M
Decreased number of pyramidal
cells in hippocampus
5 x 1(T5
BMDL
0.016
300
He et al,
(2008)
Subchronic p-RfC
(mg/m3)
NDr
Chronic p-RfC
(mg/m3)
NDr
BMDL = benchmark dose lower confidence limit; La = lanthanum; M = male(s); NDr = not determined;
POD = point of departure; p-RfC = provisional reference concentration; p-RfD = provisional reference dose;
UFC = composite uncertainty factor.
Table 7. Summary of Cancer Reference Values for Soluble Lanthanum
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)-1
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
DERIVATION OF ORAL REFERENCE DOSES
Derivation of a Subchronic Provisional Reference Dose
Studies pertinent to the derivation of a subchronic provisional reference dose (p-RfD) for
soluble lanthanum include a 18-day study of dietary lanthanum chloride in rats (He et al.. 2003).
a 4-week rat gavage study of lanthanum chloride published in Japanese (Ogawa, 1992). a
3-month mouse gavage study of lanthanum chloride examining renal endpoints (Zhao et al..
2013). a 3-month rat gavage study of lanthanum nitrate (Fane et al.. 2018). three 5-6-month
studies of rats exposed by gavage to lanthanum chloride (Feng et al.. 2006b) or lanthanum nitrate
(Huang et al.. 2006; Chen et al.. 2003). and 1 1 studies of rats or mice exposed during premating,
gestation, lactation, and/or postnatally to lanthanum chloride either in drinking water (Jin et al..
2017; Zhang et al.. 2017; Liu et al.. 2014; Yang et al.. 2013; Zheng et al.. 2013; ] lao et al.. 2012;
Yang et al.. 2009; B finer et al.. 2000) or by gavage (He et al.. 2008; Feng et al.. 2006a). The
neurodevelopmental study by He et al. (2008) is selected as the principal study for deriving a
subchronic p-RfD for soluble lanthanum salts, as described below.
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Justification of the Critical Effect
A number of studies (Jin et al.. 2017; Zhang et ai, 2017; Liu et al.. 2014; Yang et ai,
2013; Zheng et al, 2013; Yang et ah, 2009; He et ah, 2008; Feng et ah, 2006a; Feng et ah,
2006b; B riner et ah, 2000) have identified the CNS as a sensitive target of lanthanum chloride
exposure, with LOAELs as low as 1 mg La/kg-day (Fie et ah. 2008). These studies identify a
consistent pattern of impaired spatial learning and memory, as measured by Morris water maze
performance. The neurobehavioral changes are supported by findings of morphological and
histological changes in the hippocampus, the part of the brain involved in memory and
navigation. Gestational and/or postnatal exposure to lanthanum chloride was observed to result
in decreased numbers of hippocampal pyramidal cells, neural degeneration, and alterations in the
morphology of hippocampal synapses (Jin et ah. 2017; Zhang et ah, 2017; Liu et ah, 2014; Yang
et ah. 2013; Zheng et ah, 2013; Yang et ah. 2009; He et al.. 2008). The neurodevelopmental
studies in particular provide both functional and structural evidence of neurotoxicity. In
addition, several of these studies evaluated mechanistic endpoints providing additional evidence
for the relationship between exposure to lanthanum chloride and neurotoxicity as discussed in
the "Mode-of-Action/Mechanistic Studies" section.
There is some evidence for an effect of soluble lanthanum salts on the liver, albeit at
higher doses than the most sensitive measures of CNS impairment. Hepatic lesions
(inflammatory lesions and disturbances of the hepatocyte cord arrangements) were observed at
7.26 mg La/kg-day in a 6-month study of rats (Chen et ah. 2003). The lesions were accompanied
by a twofold increase in serum ALP at the same dose, although no changes in ALT, AST, or
GGT were observed. Fang et ah (2018) reported increases in serum ALT (55%) and AST (38%)
in female rats exposed to 61.6 mg La/kg-day for 3 months. He et ah (2003) observed a
50% increase in serum ALP and a twofold increase in serum ALT in rats exposed to
5.17 mg La/kg-day for 18 days. Ogawa (1992) found significant increases in serum ALT and
AST at 374 mg La/kg-day in rats treated by gavage for 28 days. Additional support for the liver
as a target of lanthanum toxicity is available in short-term-duration studies of mice (Fei et ah.
2011) and rats (Kadas et ah. 1974; Kadas et ah. 1973; Kadas and Jobst. 1973) exposed by
injection routes (see Table 4B). Other effects of lanthanum chloride exposure reported in the
available studies include decreased body weight (Jin et ah. 2017; Zhang et ah. 2017; Feng et ah.
2006a) and impaired olfactory function (Hao et ah. 2012). These effects occurred at doses
>20 mg La/kg-day, so these endpoints were not considered the most sensitive effects for use in
deriving the provisional reference values.
Justification of the Principal Study
Among the studies that identified neurobehavioral and neurodevelopmental effects of
lanthanum chloride exposure (Jin et ah. 2017; Zhang et ah. 2017; Liu et ah. 2014; Yang et ah.
2013; Zheng et ah. 2013; Yang et ah. 2009; He et ah. 2008; Feng et ah. 2006a; Feng et ah.
2006b; B riner et ah, 2000), gavage administration was used in three studies (He et ah, 2008;
Feng et ah. 2006a; Feng et ah. 2006b). while the remaining studies (Jin et ah. 2017; Zhang et ah.
2017; Liu et ah. 2014; Yang et ah. 2013; Zheng et ah. 2013; Yang et ah. 2009; B riner et ah.
2000) used drinking water administration. The drinking water studies identified LOAELs that
were higher (115.3-308.6 mg La/kg-day) than those identified in gavage studies
(1-23 mg La/kg-day). None of the drinking water studies identified a NOAEL, but the LOAELs
are too high to consider as the basis for the p-RfD point of departure (POD). In contrast, both
Feng et ah (2006a) and He et ah (2008) identified both LOAELs and NOAELs in a much lower
range.
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For the study by Feng et al. (2006a). a LOAEL of 23 nig La/kg-day was identified for
decreased body weight, decreased swimming endurance, and increased escape latency in the
Morris water maze; the NOAEL was 1 mg La/kg-day. For the study by He et al. (2008), a
LOAEL of 1 mg La/kg-day and NOAEL of 0.06 mg La/kg-day were identified for increased
general path length and decreased preference for target quadrant in the Morris water maze, as
well as decreased numbers of pyramidal cells in the hippocampus. Although decreased body
weight could potentially influence the outcome of behavioral tasks, body weights of the pups
were not affected by exposure to lanthanum chloride for 6 months. Thus, the observed
neurobehavioral changes in He et al. (2008) were not likely to be confounded by effects on body
weight. The study by He et al. (2008) identified a lower, more sensitive LOAEL and was
therefore selected as the principal study for neurobehavioral effects.
Approach for Deriving the Subchronic p-RfD
The most sensitive neurodevelopmental endpoints in the principal study were two
measures of performance in the Morris water maze (length of pathway to platform and
preference for the target quadrant) and the numbers of pyramidal cells in the CA3 region of the
hippocampus. All endpoints were subjected to benchmark dose (BMD) modeling to identify
candidate PODs for deriving the subchronic p-RfD (see Appendix C), and the dose-response data
are presented in Table B-14.
Candidate PODs, including BMDs and benchmark dose lower confidence limits
(BMDLs), resulting from the best-fitting models of data from He et al. (2008) are shown in
Table 8.
Table 8. Candidate PODs for the Subchronic p-RfD for Soluble Lanthanum
Endpoint"
Dose (mg La/kg-d)
BMR
NOAEL
LOAEL
BMD
BMDL
Decreased number of pyramidal cells in CA3 area of
hippocampus (number/mm2)
0.06
1
0.083
0.016
1 SD
Increased length general path in Morris water maze (cm)
0.06
1
2.46
0.70
1 SD
Decreased preference for target quadrant in Morris water
maze (percentage of time spent in target quadrant)
0.06
1
0.93
0.11
1 SD
•'1 lc ct al. (2008).
BMD = benchmark dose; BMDL = benchmark dose lower confidence limit; BMR = benchmark response;
La = lanthanum; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level;
POD = point of departure; p-RfD = provisional reference dose; SD = standard deviation.
The lowest candidate POD was the BMDL for decreased number of pyramidal cells in
the hippocampus (He et al.. 2008); this value (0.016 mg La/kg-day) is selected as the POD for
the subchronic p-RfD. The BMDL was not converted to a human equivalent dose (HED), as
such a conversion is not appropriate when neonatal and/or juvenile animals are directly exposed
to the test chemical.
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The subchronic p-RfD for soluble lanthanum is derived using the POD of
0.016 mg La/kg-day and a composite uncertainty factor (UFc) of 300 (reflecting an interspecies
uncertainty factor [UFa] of 10, an intraspecies uncertainty factor [UFh] of 10, and a database
uncertainty factor [UFd] of 3):
Subchronic p-RfD = POD ^ UFc
for Soluble Lanthanum = 0.016 mg La/kg-day ^ 300
= 5 x 10"5 mg La/kg-day
Table 9 summarizes the uncertainty factors for the subchronic p-RfD for soluble
lanthanum.
Table 9. Uncertainty Factors for the Subchronic p-RfD for Soluble Lanthanum
UF
Value
Justification
UFa
10
A UFa of 10 is applied to account for uncertainty associated with extrapolating from animals to
humans.
UFd
3
A UFd of 3 is applied to account for deficiencies in the toxicity database for soluble lanthanum
salts. The database includes 3-. 5- and 6-mo studies (Zhao et aL 2013; Feng et aL 2006b: Huang et
aL 2006; Chen et aL 2003) that examined comprehensive toxicity enduoints. The database also
includes several developmental studies, but none has examined teratogenicity. Furthermore, no
studies have examined reproductive endpoints.
UFh
10
A UFh of 10 is applied to account for intraspecies variability in susceptibility in the absence of
quantitative information to assess the toxicokinetics and toxicodynamics of in humans.
UFl
1
A UFl of 1 is applied because the POD is a BMDL.
UFS
1
A UFS of 1 is applied because a developmental study was selected as the principal study.
UFC
300
Composite UF = UFA x UFD x UFH x UFL XUFS.
BMDL = benchmark dose lower confidence limit; LOAEL = lowest-observed-adverse-effect level;
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfD = provisional reference dose;
UF = uncertainty factor; UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database
uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor;
UFS = subchronic-to-chronic uncertainty factor.
Confidence in the subchronic p-RfD for soluble lanthanum is low as described in
Table 10.
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Table 10. Confidence Descriptors for the Subchronic p-RfD for Soluble Lanthanum
Confidence Categories
Designation
Discussion
Confidence in principal study
M
Confidence in the orinciral studv is medium. He et al. (2008) is
a peer-reviewed study using three nonzero dose groups of
10 dams/dose. The study investigated both structural (number of
pyramidal cells in the hippocampus) and functional (Morris
water maze performance) measures of neurodevelopment, and
both LOAEL and NOAEL doses were identified. Deficiencies
in the study include the lack of information on litter distribution
of the offspring selected for testing in the Morris water maze and
the small numbers of offspring (4/group) examined for number
of pyramidal cells in the hippocampus.
Confidence in database
M
Confidence in the database is medium. The database for soluble
lanthanum salts includes 18-d, 28-d, and 3-, 5- or 6-mo studies in
rats, a 90-d study in mice, 10 developmental studies in rats
examining neurodevelopmental and olfactory endpoints, and a
single neurodevelopmental study in mice. There are no studies
of potential teratogenicity in humans or animals exposed orally,
althoueh an i.a studv (Abramczuk. 1985) showed effects on
pregnancy maintenance and litter size. Standard developmental
toxicity studies of soluble lanthanum salts are needed.
Furthermore, no studies have examined reproductive endpoints.
Confidence in subchronic p-RfDa
M
Overall confidence in the subchronic p-RfD is medium.
aThe overall confidence cannot be greater than the lowest entry in the table.
i.p. = intraperitoneal; L = low; LOAEL = lowest-observed-adverse-effect level; M = medium;
NOAEL = no-observed-adverse-effect level; p-RfD = provisional reference dose.
Derivation of a Chronic Provisional Reference Dose
No studies of soluble lanthanum with exposure duration longer than 6 months have been
identified in the literature. Therefore, the POD for neurodevelopmental effects in the study by
He et al. (2008) is selected as the basis for the chronic p-RfD. Because the principal study
included gestational exposure, an uncertainty factor for duration extrapolation was not included.
Therefore, the chronic p-RfD for soluble lanthanum (5 x 10"5 mg La/kg-day) is the same as
the subchronic p-RfD. The uncertainty factors for the chronic p-RfD are the same as those
shown in Table 9.
The chronic p-RfD for soluble lanthanum was derived using the POD of
0.016 mg La/kg-day and a UFc of 300 (reflecting a UFa of 10, a UFh of 10, and a UFd of 3):
Chronic p-RfD = POD UFc
for Soluble Lanthanum = 0.016 mg La/kg-day ^ 300
= 5 x 10"5 mg La/kg-day
Table 11 summarizes the uncertainty factors for the chronic p-RfD for soluble lanthanum
salts.
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Table 11. Uncertainty Factors for the Chronic p-RfD for Soluble Lanthanum Salts
UF
Value
Justification
UFa
10
A UFa of 10 is applied to account for uncertainty associated with extrapolating from animals to
humans.
UFd
3
A UFd of 3 is applied to account for deficiencies in the toxicity database for soluble lanthanum
salts. The database includes 3-. 5- and 6-mo studies (Zhao et aL 2013; Feng et aL 2006b: Huang et
aL 2006; Chen et aL 2003) that examined comprehensive toxicity endnoints. The database also
includes several developmental studies, but none has examined teratogenicity. Furthermore, there
are no studies of reproductive endpoints.
UFh
10
A UFh of 10 is applied to account for intraspecies variability in susceptibility in the absence of
quantitative information to assess the toxicokinetics and toxicodynamics of in humans.
UFl
1
A UFl of 1 is applied because the POD is a BMDL.
UFS
1
A UFS of 1 is applied because a developmental study was selected as the principal study.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMDL = benchmark dose lower confidence limit; LOAEL = lowest-observed-adverse-effect level;
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfD = provisional reference dose;
UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database
uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor;
UFS = subchronic-to-chronic uncertainty factor.
Confidence in the chronic p-RfD for soluble lanthanum is medium as described in
Table 12.
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Table 12. Confidence Descriptors for the Chronic p-RfD for Soluble Lanthanum Salts
Confidence Categories
Designation
Discussion
Confidence in principal study
M
Confidence in the orinciDal studv is medium. He et al. (2008) is
a peer-reviewed study using three nonzero dose groups of
10 dams/dose. The study investigated both structural (number of
pyramidal cells in the hippocampus) and functional (Morris
water maze performance) measures of neurodevelopment, and
both LOAEL and NOAEL doses were identified. Deficiencies
in the study include the lack of information on litter distribution
of the offspring selected for testing in the Morris water maze and
the small numbers of offspring (4/group) examined for number
of pyramidal cells in the hippocampus.
Confidence in database
M
Confidence in the database is medium. The database for soluble
lanthanum salts includes 18-d, 28-d, and 3-, 5- or 6-mo studies in
rats, a 90-d study in mice, 10 developmental studies in rats
examining neurodevelopmental and olfactory endpoints, and a
single neurodevelopmental study in mice. There are no studies
of potential teratogenicity in humans or animals exposed orally,
althoueh an i.a studv (Abramczuk. 1985) showed effects on
pregnancy maintenance and litter size. Standard developmental
toxicity studies of soluble lanthanum salts are needed.
Furthermore, no studies have examined reproductive endpoints.
Confidence in chronic p-RfDa
M
Overall confidence in the chronic p-RfD is medium.
aThe overall confidence cannot be greater than the lowest entry in the table.
i.p. = intraperitoneal; L = low; LOAEL = lowest-observed-adverse-effect level; M = medium;
NOAEL = no-observed-adverse-effect level; p-RfD = provisional reference dose.
Because the fundamental determinant of the toxicity of soluble lanthanum compounds is
expected to be due to lanthanum metal itself, the toxicity of such soluble compounds is directly
related to the relative molecular weight contribution from lanthanum. Therefore, the subchronic
and chronic p-RfDs derived above for soluble lanthanum are applicable to soluble lanthanum
compounds (e.g., salts) following application of a molecular-weight adjustment and appropriate
stoichiometric calculations.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No pertinent data regarding the toxicity of repeated inhalation exposure to soluble
lanthanum have been located in the available literature. Derivation of a provisional reference
concentration (p-RfC) for soluble lanthanum is precluded by the lack of appropriate inhalation
toxicity data.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
No carcinogenicity data have been located for soluble lanthanum. Genotoxicity studies
of lanthanum chloride, lanthanum nitrate, and lanthanum acetate are available; these studies are
limited, but available data suggest that lanthanum nitrate may be genotoxic in human
lymphocytes (Yongxing et al.. 2000). The cancer weight-of-evidence (WOE) descriptor for
soluble lanthanum salts is "Inadequate Information to Assess Carcinogenic Potential" as
presented in Table 13.
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Table 13. Cancer WOE Descriptor for Soluble Lanthanum
Possible WOE Descriptor
Designation
Route of Entry
(oral, inhalation, or both)
Comments
"Carcinogenic to Humans "
NS
NA
There are no human data to support
this.
"Likely to Be Carcinogenic to
Humans "
NS
NA
There are no animal studies to support
this.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
There are no animal studies to support
this.
"Inadequate Information to
Assess Carcinogenic Potential"
Selected
Both
No studies are available that
evaluated carcinogenicity effects in
humans or animals exposed to
soluble lanthanum.
"Not Likely to Be Carcinogenic
to Humans "
NS
NA
No evidence of noncarcinogenicity is
available.
NA = not applicable; NS = not selected; WOE = weight of evidence.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of quantitative estimates of cancer risk for soluble lanthanum is precluded by
the lack of data demonstrating carcinogenicity associated with exposure to soluble lanthanum.
57
Soluble Lanthanum
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09-27-2018
APPENDIX A. SCREENING PROVISIONAL VALUES
No provisional screening values are derived.
58
Soluble Lanthanum
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09-27-2018
APPENDIX B. DATA TABLES
Table B-l. Serum Chemistry Changes in Wistar Rats Exposed to Lanthanum Chloride
Hexahydrate in the Diet for 18 Days3'b
Dose (mg La/kg-d)
Endpoint
0
2.6
5.17
ALT (U/L)
24.4
44.3* (82)
57* (134)
ALP (U/L)
209
254 (22)
328* (57)
•'11c ct al. (2003).
bData reported as mean (percent change compared with control); % change control = ([treatment mean - control
mean] control mean) x 100; n = 10/group.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
ALP = alkaline phosphatase; ALT = alanine aminotransferase; La = lanthanum.
59
Soluble Lanthanum
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Table B-2. Selected Clinical Chemistry Results in SlcrWistar Rats Exposed to Lanthanum Chloride Heptahydrate by Gavage for
28 Days"'b
Endpoint
Dose (mg La/kg-d)
Groups Sacrificed after Exposure
Recovery Groups
0
15
74.8
374
Pair-Fed Control
0
374
Male
Total protein (g/dL)
6.3 ±0.09
6.23 ±0.1
(-1.1)
6.04 ±0.25
(-4.1)
5.69 ± 0.23**-#
(-9.7)
5.98 ±0.12**
(-5.1)
6.38 ±0.08
6.13 ±0.15*
(-3.9)
BUN (mg/dL)
20.1 ±2.7
20.1 ±2
(0)
18.2 ± 1.8
(-9.5)
18.6 ±3.6##
(-7.5)
12.6 ±0.7**
(-37)
20.5 ±2.5
20.8 ± 1.7
(+1.5)
Creatinine (mg/dL)
0.42 ± 0.02
0.42 ±0.02
(0)
0.44 ±0.05
(+4.8)
0.44 ±0.07
(+4.8)
0.43 ±0.03
(+2.4)
0.47 ±0.04
0.41 ±0.05
(-12.8)
Uric acid (mg/dL)
0.95 ±0.18
1.14 ±0.4
(+20)
1.1 ±0.2
(+15.8)
1.05 ±0.35
(+10.5)
0.7 ±0.12*
(-26)
0.74 ±0.22
0.73 ±0.06
(-1.4)
ALT (mU/mL)
48 ±2
51 ±5
(+6.3)
58 ±6*
(+20.8)
105 ± 34*-#
(+118.8)
41 ±7
(-15)
52 ±7
55 ±9
(+5.8)
AST (mU/mL)
75 ±4
75 ±3
(0)
80 ±5
(+6.7)
98 ± 12**-m
(+30.7)
68 ±9
(-9.3)
74 ± 11
75 ± 13
(+1.4)
Cholinesterase (mU/mL)
172 ± 26
156 ±7
(-9.3)
174 ± 18
(+1.2)
168 ± 14
(-2.3)
195 ±33
(+13)
147 ± 14
197 ± 16**
(+34)
Female
Total protein (g/dL)
5.95 ±0.11
5.89 ± 0.11
(-1)
5.87 ±0.28
(-1.3)
5.27 ± 0.24**-#
(-11.4)
5.62 ±0.05**
(-5.5)
6.24 ±0.13
6.21 ±0.1
(-0.5)
BUN (mg/dL)
18.8 ±2.4
18.2 ± 1.8
(-3.2)
16.6 ± 1.8
(-11.7)
17.2 ±3.9##
(-8.5)
10.6 ±0.8**
(-44)
16 ±0.9
17 ± 1.2
(+6.3)
Creatinine (mg/dL)
0.64 ± 0.04
0.65 ±0.02
(+1.6)
0.6 ±0.07
(-6.3)
0.61±0.02##
(-4.7)
0.48 ±0.04**
(-25)
0.51 ±0.04
0.47 ±0.02*
(-7.8)
Uric acid (mg/dL)
0.74 ±0.09
1.00 ±0.18*
(+35.1)
0.96 ±0.14*
(+29.7)
1.03 ± 0.2*-m
(+39.2)
0.51 ±0.08**
(-31)
0.49 ±0.11
0.64 ±0.14
(+30.6)
ALT (mU/mL)
47 ± 10
52 ±7
(+10.6)
44 ±4
(-6.4)
72 ± 7**'m
(+53.2)
35 ±5
(-26)
43 ±9
49 ± 13
(+14)
60
Soluble Lanthanum
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09-27-2018
Table B-2. Selected Clinical Chemistry Results in SlcrWistar Rats Exposed to Lanthanum Chloride Heptahydrate by Gavage for
28 Days"'b
Endpoint
Dose (mg La/kg-d)
Groups Sacrificed after Exposure
Recovery Groups
0
15
74.8
374
Pair-Fed Control
0
374
AST (mU/mL)
82 ±4
79 ±2
(-3.7)
90 ± 11
(+9.8)
92 ± 5**'""
(+12.2)
76 + 9
(-7.3)
69 + 8
75 + 6
(+8.7)
Cholinesterase (mU/mL)
1,022 ± 89
1,001 ± 196
(-2.1)
760±150**
(-25.6)
348 + 34**'""
(-65.9)
651 + 94**
(-36)
1,275 + 149
976 + 195*
(-23.5)
•Qgavva (1992).
bData reported as mean ± SD (percent change compared with untreated control); % change control = ([treatment mean - control mean] + control mean) x 100; n = 4 or
5/group.
* Statistically significantly different from untreated control (p < 0.05), as reported by the study authors.
**Statistically significantly different from untreated control (p < 0.01), as reported by the study authors.
"Statistically significantly different from pair-fed control (p < 0.05), as reported by the study authors.
""Statistically significantly different from pair-fed control (p < 0.01), as reported by the study authors.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; La = lanthanum; SD = standard deviation.
61
Soluble Lanthanum
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09-27-2018
Table B-3. Selected Histopathology Results in SlcrWistar Rats Exposed to Lanthanum
Chloride Heptahydrate by Gavage for 28 Days"'b
Endpoint
Dose (mg La/kg-d)
Groups Sacrificed after Exposure
Recovery Groups
0
15
74.8
374
0
374
Male
Lung granulation
0/5
0/5
4/5*
4/5*
0/5
2/4
Lung giant cell appearance
0/5
0/5
4/5*
4/5*
0/5
2/4
Lung eosinocyte infiltration
0/5
0/5
2/5
3/5
0/5
0/4
Lung alveolar wall thickening
0/5
1/5
0/5
0/5
0/5
0/4
Stomach (forestomach) hyperkeratosis
0/5
0/5
0/5
2/5
0/5
0/4
Stomach (glandular) erosion
0/5
0/5
0/5
3/5
0/5
0/4
Stomach (glandular) dilatation of acinus
0/5
0/5
0/5
4/5*
0/5
0/4
Stomach (glandular) epithelium swelling
0/5
0/5
0/5
0/5
0/5
0/4
Stomach (submucosa) eosinocyte infiltration
0/5
0/5
0/5
4/5*
0/5
0/4
Female
Lung granulation
0/5
1/5
5/5**
1/5
0/5
3/5
Lung giant cell appearance
0/5
1/5
4/5*
1/5
0/5
2/5
Lung eosinocyte infiltration
0/5
0/5
2/5
0/5
0/5
0/5
Lung alveolar wall thickening
0/5
2/5
0/5
4/5*
0/5
0/5
Stomach (forestomach) hyperkeratosis
0/5
1/5
1/5
5/5**
0/5
1/5
Stomach (glandular) erosion
0/5
0/5
0/5
0/5
0/5
1/5
Stomach (glandular) dilatation of acinus
0/5
0/5
0/5
0/5
0/5
0/5
Stomach (glandular) epithelium swelling
0/5
0/5
0/5
4/5*
0/5
0/5
Stomach (submucosa) eosinocyte infiltration
0/5
0/5
0/5
5/5**
0/5
0/5
aQgawa (1992). Data for pair-fed controls were not reported.
bData reported as incidence (number affected/number examined).
* Statistically significantly different from untreated control (p < 0.05), as reported by the study authors.
**Statistically significantly different from untreated control (p < 0.01), as reported by the study authors.
La = lanthanum.
62
Soluble Lanthanum
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09-27-2018
Table B-4. Serum Chemistry Changes in Male ICR Mice Exposed to Lanthanum Chloride
by Gavage for 90 Days"'b
Endpoint
Dose (mg La/kg-d)
0
1
3
5.7
Uric acid (|imol/L)
222.56 ± 11.13
160.21 ±8.01* (-28)
110.88 ±5.54** (-50.2)
96.76 ±4.84*** (-56.5)
Creatinine (|imol/L)
8.81 ±0.44
9.75 ± 0.49° (+10.7)
11.68 ±0.58** (+32.6)
13.19 ±0.66*** (+49.7)
BUN (mmol/L)
9.28 ±0.46
8.11 ±0.41° (-2.1)
7.05 ±0.35** (-14.9)
6.32±0.32*** (-23.7)
Calcium (mmol/L)
2.79 ±0.14
2.58 ± 0.13° (-7.5)
2.41 ±0.12** (-13.6)
2.12 ±0.11*** (-24)
Phosphorus (mmol/L)
3.68 ±0.18
3.52 ±0.18c (-4.3)
3.40 ±0.17** (-7.6)
3.18 ±0.16** (-13.6)
aZfaao et al. (2013).
bData reported as mean ± SEM (percent change compared with control); % change control = ([treatment
mean - control mean] + control mean) x 100; n = 5/group.
°Not statistically significantly different from control by t-test performed for this review. Positive statistical results
reported by the study authors appeared suspect upon initial visual inspection and could not be subsequently
duplicated.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
**Statistically significantly different from control (p < 0.01), as reported by the study authors.
***Statistically significantly different from control (p < 0.001), as reported by the study authors.
BUN = blood urea nitrogen; La = lanthanum; SEM = standard error of the mean.
Table B-5. Organ Weights of Male S-D Rats Exposed to Lanthanum Nitrate by Gavage for
90 Days3'b
Endpoint
Dose (mg La/kg-d)
0
0.64
2.6
10.3
61.6
Liver (g)
11.525 ±0.96
11.208 ± 1.12
(-2.8)
10.765 + 0.95
(-6.6)
10.576 + 2.87
(-8.2)
8.494+ 1.35*
(-26)
Spleen (g)
0.810 ±0.05
0.815 ±0.10
(+0.6)
0.790 + 0.15
(-2.4)
0.739 + 0.79
(-8.8)
0.637 + 0.17*
(-21)
Kidney (g)
2.870 ± 0.20
2.876 + 0.23
(+0.2)
2.861 + 0.29
(-0.3)
2.718 + 0.27
(-5.3)
2.250 + 0.30*
(-22)
Heart (g)
1.466 ±0.11
1.495 + 0.11
(+2.0)
1.508 + 0.18
(+2.9)
1.386 + 0.11
(-5.5)
1.210 + 0.07*
(-17)
Thymus (g)
0.370 ±0.10
0.330 + 0.07
(-11)
0.385 + 0.10
(+4.1)
0.303 + 0.07
(-18)
0.269 + 0.07*
(-27)
aOeawa (1992).
bData reported as mean ± SD (percent change compared with untreated control); % change control = ([treatment
mean - control mean] + control mean) x 100; n = 10/group.
* Statistically significantly different from untreated control (p < 0.05), as reported by the study authors.
La = lanthanum; SD = standard deviation; S-D = Sprague-Dawley.
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Soluble Lanthanum
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Table B-6. Selected Clinical Chemistry Results in Female S-D Rats Exposed to
Lanthanum Nitrate by Gavage for 90 Days"'b
Endpoint
Dose (mg La/kg-d)
Groups Sacrificed after Exposure
Recovery Groups
0
0.64
2.6
10.3
61.6
0
61.6
ALT (U/L)
21.0 ±5.2
21.5 ±5.7
(+0.1)
24.0 + 6.5
(+14)
24.2 + 6.6
(+15)
32.6 + 9.9*
(+55)
30 + 4.65
34 + 6.9
(+13)
AST (U/L)
65.8 ±22.1
64.0 ±20.9
(-2.7)
76.2+13.8
(+16)
72.2+18.2
(+9.7)
91.1 + 17.8*
(+38)
82.4 + 4.1
98.2 + 3.8
(+19)
Glucose (mmol/L)
5.7 ± 1.4
6.3 ±0.6
(+11)
6.2+1.0
(+8.7)
6.3 + 1.3
(+11)
7.0 + 0.8*
(+23)
6.3 + 1.3
6.9+1.2
(+9.5)
Urea (mmol/L)
5.0 ±0.7
5.1 ± 0.6
(+2.0)
5.4 + 0.6
(+8.0)
5.8+1.3
(+16)
6.4+1.1*
(+28)
6.4+1.0
5.7 + 0.8
(-11)
Creatinine (|imol/L)
28.8 ± 10.4
36.7±11.2
(+27)
37.1 + 8.9
(+29)
35.0+12.2
(+22)
41.6 + 9.2*
(+44)
26.4 + 5.6
24.3 + 2.4
(-8.0)
Ca (mmol/L)
1.7 ±0.4
1.7 + 0.3
(0)
1.9 + 0.4
(+12)
1.9 + 0.3
(+12)
2.1 + 0.3*
(+24)
2.4 + 0.02
2.3 + 0.03
(-0.42)
aOeawa (1992).
bData reported as mean ± SD (percent change compared with untreated control); % change control = ([treatment
mean - control mean] + control mean) x 100; n = 10/group.
* Statistically significantly different from untreated control (p < 0.05), as reported by the study authors.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SD = standard deviation;
S-D = Sprague-Dawley.
Table B-7. Neurotransmitter Concentrations in Brains of Male Wistar Rats Exposed to
Lanthanum Chloride by Gavage for 5 Months"'b
Endpoint
Dose (mg La/kg-d)
0
0.06
1
23
Dopamine (ng/g brain tissue)
503.1 + 53.5
468.7 + 81.2
(-6.8)
432.6+ 131.8
(-14)
389.9 + 74.6*
(-22.5)
Dihydroxyphenylacetic acid (ng/g brain tissue)
180.2 + 41.3
158.4 + 37.2
(-12.1)
144.5 + 26.3
(-19.8)
141.1 + 30.1*
(-21.7)
5-HT (ng/g brain tissue)
142.4 + 34.7
115.1 + 26.2
(-19.2)
109.7 + 31.5*
(-23)
109.9+14.3*
(-22.8)
Norepinephrine (ng/g brain tissue)
312.8 + 44
305.5 + 46.9
(-2.3)
271.5 + 84.9
(-13.2)
224.7 + 87.1*
(-28.2)
aFeng et al. (2006b).
bData reported as mean ± SD (percent change compared with control); % change control = ([treatment
mean - control mean] + control mean) x 100; n = 10/group.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
5-HT = 5-hydroxytryptamine; La = lanthanum; SD = standard deviation.
64
Soluble Lanthanum
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FINAL
09-27-2018
Table B-8. Selected Results in Wistar Rats Exposed to Lanthanum Nitrate by Gavage for 6 Months
a, b
Dose (mg La/kg-d)
Endpoint
0
0.036
0.073
0.73
3.63
7.26
Male
Relative liver weight0 (%)
2.83 ±0.55
3.06 ±0.39 (+8.1)
2.99 ±0.41 (+5.7)
2.8 + 0.31 (-1.1)
2.44 + 0.44 (-14)
3.03 + 0.56 (7.1)
Serum ALPd(IU/L)
99.13 ±27.51
177.65 ±34.94***
(+79)
148.44 ±52.86**
(+50)
169.75 ±53.64***
(+71)
123.11 + 71.04
(+24)
221.17 + 64.35***
(+123)
Female
Relative liver weight0 (%)
3.4 ±0.28
2.65 ±0.28* (-22.1)
3.69 ±0.40 (+8.5)
3.54 + 0.33 (+4.1)
3.54 + 0.26 (+4.1)
3.65 + 0.41 (+7.4)
Serum ALPd(IU/L)
162.02 ±61.58
157.74 ±28.43
(-2.6)
202.61 + 39.27
(+25)
160.46 + 41.48
(-1)
191.48 + 59.80
(+18.2)
166.75 + 34.64
(+2.9)
"Chen et at. (2003).
bData reported as mean ± SD (percent change compared with control); % change control = ([treatment mean - control mean] + control mean) x 100.
°Group sizes were 13/dose.
dGroup sizes were 13/dose.
* Statistically significantly different from control (p < 0.05), by t-test performed for this review. Negative statistical result reported by the study authors appeared suspect
upon initial visual inspection and could not be subsequently duplicated.
**Statistically significantly different from control (p < 0.01), by t-test performed for this review.
***Statistically significantly different from control (p < 0.001), by /-test performed for this review.
ALP = alkaline phosphatase; La = lanthanum; SD = standard deviation.
65
Soluble Lanthanum
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FINAL
09-27-2018
Table B-9. Bone Mineral Composition in Male Wistar Rats Exposed to Lanthanum
Nitrate by Gavage for 6 Months"'b
Endpoint
Dose (mg La/kg-d)
0
0.85
Calcium (%)
24.9 ±0.6
22 ±0.8* (-11.6)
Phosphorus (%)
11.4 ±0.6
9.5 ±0.4* (-16.7)
Ratio of Ca:P (molar)
1.69 ±0.08
1.83 ±0.11 (+8.3)
Carbonate (%)
4.4 ±0.3
6.2 ± 0.4* (+40.9)
Mineral matrix (w/w)
5 ±0.3
4.5 ±0.2* (-10)
"Huang et al. (2006).
bData reported as mean ± SEM (percent change compared with control); % change control = ([treatment
mean - control mean] + control mean) x 100; n = 10/group.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
Ca = calcium; La = lanthanum; P = phosphorus; SEM = standard error of the mean.
Table B-10. Olfactory Function in Offspring of Wistar Rats Exposed to Lanthanum
Chloride by Drinking Water from GD 7 to PND 21a'b
Endpoint
Dose (mg La/kg-d)
0
230.6
Buried food pellet test latency
Trial 1 (s)
45.01±9.04
85.73 ± 13.18* (+90.5)
Trial 2 (s)
39.22 ±6.37
66.30 + 7.82* (+69)
Trial 3 (s)
36.6 ±5.26
62.28 + 6.09* (+70.2)
Visible food pellet (s)
20.43 ±3.61
22.19 + 3.88 (+8.6)
Olfactory maze test latency
Trial 1 (s)
67.25 ±6.12
93.07 + 6.38* (+38.4)
Trial 2 (s)
53.36 ±5.75
76.27 + 5.97* (+42.9)
Trial 3 (s)
48.05 ±5.27
70.12 + 6.03* (+45.9)
Visible food pellet (s)
46.13 ±5.31
49.04 + 4.95 (+6.3)
aHao et al. (2012).
bData reported as mean ± SEM (percent change compared with control); % change control = ([treatment
mean - control mean] + control mean) x 100; n = 8/group.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
GD = gestation day; La = lanthanum; PND = postnatal day; SEM = standard error of the mean.
66
Soluble Lanthanum
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FINAL
09-27-2018
Table B-ll. Brain- and Body-Weight Changes in Wistar Rat Pups Exposed to Lanthanum
Chloride during Gestation and Lactation and via Drinking Water for 1 Month3'b
Endpoint
Dose (mg La/kg-d)
0
230.6 (maternal)
307.5 (pup)
461 (maternal)
615(pup)
923 (maternal)
1,230 (pup)
Body weight (g)
176.25 ± 15.29
164.38 ± 11.31
(-6.7)
147.38 ± 13.65*
(-16.4)
120.75 ± 14.64*
(-31.5)
Brain weight (g)
1.73 ±0.09
1.56 ±0.510
(-9.8)
1.41 ±0.19*
(-18.5)
1.19 ± 0.13*
(-31.2)
Brain weight coefficient (%)
0.98 ±0.04
0.95 ±0.06
(-3.1)
0.96 ±0.12
("2)
1 ±0.13
(+2)
"Zheng et al. (2013).
bData reported as mean ± SD (percent change compared with control); % change control = ([treatment
mean - control mean] control mean) x 100; n = 8/group.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
La = lanthanum; SD = standard deviation.
Table B-12. Body-Weight and Brain Changes in Wistar Rat Pups Exposed to Lanthanum
Chloride during Gestation and Lactation and via Drinking Water for 2 Months3'b
Endpoint
Dose (mg La/kg-d)
0
115.3 (maternal)
153.7 (pup)
230.6 (maternal)
307.5 (pup)
461 (maternal)
615(pup)
Body weight (g)
291.0 ±27.0
260.2 ± 48.2
(-10.6)
257.0 ±29.1
(-11.7)
241.9 ±51.7*
(-31.5)
Brain weight (g)
1.78 ±0.082
1.66 ±0.119*
(-6.7)
1.65 ±0.82*
(-7.3)
1.62 ±0.87*
(-9.0)
Brain coefficient (%)
0.614 ±0.038
0.650 ± 0.067
0.646 ± 0.054
0.676 ±0.102
Hippocampus weight (g)
0.124± 0.013
0.115 ± 0.017
(-7.3)
0.115 ±0.007
(-7.3)
0.113 ± 0.151
(-8.9)
Hippocampus coefficient (%)
0.043± 0.004
0.044 ± 0.003
0.045 ±0.005
0.047 ± 0.005
aZhang et al. (2017).
bData reported as mean ± SD (percent change compared with control); % change control = ([treatment
mean - control mean] control mean) x 100; n = 10/group.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
La = lanthanum; SD = standard deviation.
67
Soluble Lanthanum
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FINAL
09-27-2018
Table B-13. Selected Results in Wistar Rat Offspring Exposed to Lanthanum Chloride by
Gavage throughout Gestation and Lactation and by Gavage from PND 20 until up to
5 months of agea'b
Endpoint
Dose (mg La/kg-d)
0
0.06
1
23
Male
Body weight (g), PND 0
6.18 ±0.57
6.12 ±0.57
(-1)
6.3+0.61
(+1.9)
6.08 + 0.47
(-1.6)
Body weight (g), PND 90
444 ± 37
463 ±31
(+4.3)
479 + 28**
(+7.9)
420 + 21
(-5.4)
Body weight (g), PND 150
578 ±38
545 ± 26
(-5.7)
578 + 24
(0)
512 + 35***
(-11.4)
Surface righting reflex (s), PND 3
4.39 ±2.17
3.65 ± 1.85
(-16.9)
2.82+ 1.63**
(-35.8)
2.85+ 1.42**
(-35.1)
Surface righting reflex (s), PND 4
2.19 ±0.85
2.33 ±0.83
(+6.4)
1.81 + 0.69*
(-17.4)
1.89 + 0.67*
(-13.7)
Swimming time (s), PND 20
25.89 ±20.32
27.42 ±26.21
(+5.9)
31.76 + 25.24*
(+22.7)
13.98+ 14.86*
(-46)
Female
Body weight (g), PND 0
6.17 ±0.55
6.09±0.48
(-1.3)
6.29 + 0.62
(+1.9)
6.11 + 0.39
(-1)
Body weight (g), PND 90 (g)
278 ± 15
271 ± 16
(-2.5)
280 + 14
(+0.7)
264 + 14
("5)
Body weight (g), PND 150 (g)°
295 ± 13
285 ±11
(-3.4)
291 + 6
(-1.4)
269+ 14***
(-8.8)
Surface righting reflex (s), PND 3
4.35 ± 1.99
3.65 ± 1.98
(-16.1)
2.80+ 1.62**
(-35.6)
2.88+ 1.47**
(-33.8)
Surface righting reflex (s), PND 4
2.2 ±0.92
2.33 ±0.79
(+5.9)
1.80 + 0.58*
(-18.2)
1.86 + 0.66*
(-15.5)
Swimming time (s), PND 20
25.32 ± 18.47
29.54 + 25.31
(+16.7)
30.98 + 27.38*
(+22.4)
14.09+ 14.22*
(-44.4)
aFeng et al. (2006a).
bData reported as mean ± SD (percent change compared with control); % change control = ([treatment
mean - control mean] + control mean) x 100; n = 15/group except where noted.
°Group sizes were 6/dose for this endpoint in females.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
**Statistically significantly different from control (p < 0.01), as reported by the study authors.
***Statistically significantly different from control (p < 0.001), as reported by the study authors.
La = lanthanum; PND = postnatal day; SD = standard deviation.
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Table B-14. Pyramidal Cells in the CA3 Region of the Hippocampus and Morris Water
Maze Performance in Wistar Rat Pups Exposed to Lanthanum Chloride by Gavage from
Birth to PND 20a'b
Endpoint
Dose (mg La/kg-d)
0
0.06
1
23
Number of pyramidal cells in CA3 area of hippocampus
n
4
4
4
4
Mean
325
299
265*
243**
SD
24
24
34
29
Length general path in Morris water maze (cm) at Session 4
n
15
15
15
15
Mean
279
325
383*
493**
SD
112
157
112
202
Preference for target quadrant (percentage of time spent in target quadrant) at Session 4
n
15
15
15
15
Mean
36
35
30*
28**
SD
5.8
5.0
6.7
5.8
aHe et al. (2008)
'Data digitized from Figures IB. 1C. and 6 of He et al. (2008): presented as mean ± SD (the reported SEM was
converted to SD).
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
**Statistically significantly different from control (p < 0.01), as reported by the study authors.
La = lanthanum; PND = postnatal day; SD = standard deviation (computed as SE x a/ [n]); SE = standard error;
SEM = standard error of the mean.
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Table B-15. Representative Results, Morris Water Maze Performance in Wistar Rat Pups
Exposed to Lanthanum Chloride by Drinking Water from Birth to PND 21a'b
Endpoint
Dose (mg La/kg-d)
0
230.6 (maternal)
307.5 (pup)
461 (maternal)
615(pup)
923 (maternal)
1,230 (pup)
Escape latency, D l(s)
77.25 ± 9.25
75.13 ± 10.01
(-2.7)
80.5 + 8.80
(+4.2)
82.88 + 8.27
(+7.3)
Escape latency, D 2(s)
58.75 ± 11.16
69.50 ± 10.16*
(+18)
75.25+ 11.7*
(+28)
81.38 + 7.87*
(+39)
Escape latency, D 3(s)
40.25 ± 9.05
53 ±6.37*
(+31.7)
68.13 + 8.06*
(+69.3)
73.63 + 10.97*
(+82.9)
Escape latency, D 4(s)
32.00 ±6.23
42.25 ±4.03*
(+32)
54.50 + 3.89*
(+70.3)
57.88 + 4.73*
(+80.9)
Escape latency, D 5(s)
30.50 ±5.07
34.00±5.42
(+11.5)
37.13 + 6.71
(+21.7)
39.25 + 9.56
(+28.7)
Escape latency, D 12(s)
39.00 ±9.74
59.13 + 11.15#
(+52)
68.13 + 12.69#
(+75)
84.50 + 26.67#
(+117)
"Yang et al. (2009).
bData reported as mean ± SD (percent change compared with control); % change control = ([treatment
mean - control mean] + control mean) x 100; n = 8/group.
* Statistically significantly different from same day control (p < 0.05), as reported by the study authors.
"Statistically significantly different from Day 5 result for same group (p < 0.05), as reported by the study authors.
La = lanthanum; PND = postnatal day; SD = standard deviation.
Table B-16. Hippocampal Synaptic Ultrastructure in Wistar Rats Exposed to Lanthanum
Chloride via Lactation from Birth to PND 21 and via Drinking Water for 2 Months"'b
Endpoint
Dose (mg La/kg-d)
0
230.6 (maternal)
307.5 (pup)
461 (maternal)
615(pup)
923 (maternal)
1,230 (pup)
Thickness of postsynaptic density (nm)
75.80 + 6.1
58.96 + 3.66*
(-22.2)
47.83 + 4.63*
(-36.9)
39.28 + 5.02*
(-48.2)
Length of active zone (nm)
379.59+ 19.43
308.36+ 18.44*
(-18.8)
242.45 + 18.83*
(-36)
212.41 + 16.90*
(-44)
Synaptic curvature (ratio of the
synaptic arch length and chord length)
1.16 + 0.06
1.12 + 0.08*
(-3.4)
1.11 + 0.06*
(-4.3)
1.07 + 0.06*
(-7.8)
aLiu et al. (2014).
bData reported as mean ± SD (percent change compared with control); % change control = ([treatment
mean - control mean] + control mean) x 100; n = 50 synapses/group.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
La = lanthanum; PND = postnatal day; SD = standard deviation.
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APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODELING PROCEDURE FOR CONTINUOUS DATA
The benchmark dose (BMD) modeling of continuous data was conducted with
U.S. EPA's Benchmark Dose Software (BMDS, Version 2.5). For these data, all continuous
models available within the software were fit using a default benchmark response (BMR) of
1 standard deviation (SD) relative risk. An adequate fit was judged based on the
X2 goodness-of-fitp-walue (p> 0.1), magnitude of the scaled residuals near the BMR, and visual
inspection of the model fit. In addition to these three criteria forjudging adequacy of model fit, a
determination was made as to whether the variance across dose groups was homogeneous. If a
homogeneous variance model was deemed appropriate based on the statistical test provided by
BMDS (i.e., Test 2), the final BMD results were estimated from a homogeneous variance model.
If the test for homogeneity of variance was rejected (p< 0.1), the model was run again while
modeling the variance as a power function of the mean to account for this nonhomogeneous
variance. If this nonhomogeneous variance model adequately fit the data (i.e., Test 3;
p-w alue > 0.1), the final BMD results were estimated from a nonhomogeneous variance model.
Otherwise, the data set was considered unsuitable for BMD modeling. Among all models
providing adequate fit, the lowest benchmark dose lower confidence limit (BMDL) was selected
if the BMDLs estimated from different models varied greater than threefold; otherwise, the
BMDL from the model with the lowest Akaike's information criterion (AIC) was selected.
BMD MODELING TO IDENTIFY POTENTIAL PODS FOR THE DERIVATION OF A
SUBCHRONIC PROVISIONAL REFERENCE DOSE
The endpoints subjected to BMD modeling from the study by He et al. (2008) include
two measures of performance in the Morris water maze (length of pathway to platform and
preference for the target quadrant) and the numbers of pyramidal cells in the CA3 region of the
hippocampus. Table C-l shows the dose-response data. Summaries of modeling approaches and
results (see Tables C-2 to C-4 and Figures C-l to C-3) for each data set follow.
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Table C-l. Endpoints Subjected to BMD Modeling"
Dose (mg La/kg-d)
Endpoint
0
0.06
1
23
Number of pyramidal cells in CA3 area of hippocampus
n
4
4
4
4
Mean
325
299
265*
243**
SD
24
24
34
29
Length general path in Morris water maze (cm)
n
15
15
15
15
Mean
279
325
383*
493**
SD
112
157
112
202
Preference for target quadrant (percentage of time spent in target quadrant)
n
15
15
15
15
Mean
36
35
30*
28**
SD
5.8
5.0
6.7
5.8
'Data digitized from Figures IB, 1C. and 6 of He et al. (2008).
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
**Statistically significantly different from control (p < 0.01), as reported by the study authors.
BMD = benchmark dose; La = lanthanum; SD = standard deviation.
Decreased Numbers of Hippocampal Pyramidal Cells
The procedure outlined above was applied to the data on numbers of pyramidal cells in
the CA3 region of the hippocampus from the neurodevelopmental study by He et al. (2008)
(see Table C-l). Table C-2 summarizes the BMD modeling results. The constant variance
model provided adequate fit to the variance data. With the constant variance model applied, only
the Exponential Models 4 and 5 and the Hill model provided adequate fit to the means. The
BMDLs estimated from these models differed by less than threefold, so the model with the
lowest BMDL (Hill model) was selected. The BMD and BMDL from this model were 0.083 and
0.016 mg La/kg-day, respectively. Figure C-l shows the fit of the Hill model to the data; the
textual BMD output for this model follows the figure.
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Table C-2. BMD Model Predictions for Decreased Mean Pyramidal Cell Count in the CA3 Region of the Hippocampus in Male Rats
Exposed to Lanthanum Chloride from GD 0 through 6 Months of Agea
Model
Variance
/>-Valucb
Mean
/>-Valucb
Scaled Residual:
Dose Nearest the BMDC
AIC
BMDisd
(mg La/kg-d)
BMDLisd
(mg La/kg-d)
Constant variance
Exponential (Model 2)d
0.87
0.014
0.1008
132.57
12.314
7.193
Exponential (Model 3)d
0.87
0.014
0.1008
132.57
12.314
7.193
Exponential (Model 4)d
0.87
0.236
-0.8639
127.50
0.328
0.020
Exponential (Model 5)d
0.87
0.236
-0.8639
127.50
0.328
0.020
Hill'1 e
0.87
0.438
-0.341
126.70
0.083
0.016
Lineal
0.87
0.014
0.0825
132.63
13.046
8.042
Polynomial (2-degree/
0.87
0.014
0.0825
132.63
13.046
8.042
Polynomial (3-degree/
0.87
0.014
0.0825
132.63
13.046
8.042
Power1
0.87
0.014
0.0825
132.63
13.046
8.042
•'11c ct al. (2008).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
°Scaled residuals at doses immediately below and above the BMD; also, the largest residual at any dose.
dPower restricted to >1.
"Selected model. Constant variance model provided adequate fit to variance data. With constant variance model applied, the Exponential Models 4 and 5 and the Hill
model provided adequate fit to the means. BMDLs for models providing adequate fit were considered sufficiently close (differed by
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Hill Model, with BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
dose
14:47 01/25 2018
Figure C-l. Fit of the Hill Model to Data on Reduced Numbers of Pyramidal Cells in Rats
Exposed to Lanthanum Chloride from GD 0 to 6 Months of Age (He et al., 2008)
Text Output for Figure C-l:
Hill Model. (Version: 2.17; Date: 01/28/2013)
Input Data File:
C:/Users/j zhao/BMDS2 601/Data/hil_UntitledDatal_Hil-ConstantVariance-BMRlStd-Restrict. (
d)
Gnuplot Plotting File:
C:/Users/j zhao/BMDS2 601/Data/hil_UntitledDatal_Hil-ConstantVariance-BMRlStd-Restrict.p
It
Thu Jan 25 14:47:33 2018
BMDS Model Run
The form of the response function is:
Y[dose] = intercept + v*dose^n/(k^n + dose^n)
Dependent variable = Mean
Independent variable = Dose
rho is set to 0
Power parameter restricted to be greater than 1
A constant variance model is fit
Total number of dose groups = 4
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Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
alpha = 787.25
rho = 0 Specified
intercept = 325
v = -82
n = 0.858778
k = 0.474706
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -rho -n
have been estimated at a boundary point, or have been specified by
and do not appear in the correlation matrix )
alpha intercept v k
alpha 1 -1. 8e-007 2.9e-007 -l.le-006
intercept -1.8e-007 1 -0.63 -0.67
v 2.9e-007 -0.63 1 0.073
k -l.le-006 -0.67 0.073 1
the user,
Parameter Estimates
Interval
Variable
Limit
alpha
1037.89
intercept
349.562
v
15.1317
n
k
0.644607
Estimate
613.065
322.825
-75 . 6737
-105.331
1
0.171655
Std. Err.
216.751
13.6418
-46.016
NA
0.241307
NA - Indicates that this parameter has hit a bound
implied by some ineguality constraint and thus
has no standard error.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
188.24
296.088
-0.301297
Table of Data and Estimated Values of Interest
Dose N Obs Mean Est Mean Obs Std Dev Est Std Dev Scaled Res.
0 4 325 323 24 24.8 0.176
0.06 4 299 303 24 24.8 -0.341
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1 4 265 258 34 24.8 0.546
23 4 243 248 29 24.8 -0.381
Model Descriptions for likelihoods calculated
Model A1: Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A2: Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma(i)^2
Model A3: Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma^2
Model A3 uses any fixed variance parameters that
were specified by the user
Model R: Yi = Mu + e(i)
Var{e(i)} = Sigma^2
Likelihoods of Interest
Model
A1
A2
A3
fitted
R
Log(likelihood)
-59.046910
-58.697599
-59.046910
-59.347763
-66.903383
# Param's
5
8
5
4
2
AIC
128.093821
133.395199
128.093821
126.695526
137.806765
Explanation of Tests
Test
1:
Test
2 :
Test
3:
Test
4 :
(Note:
Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Are Variances Homogeneous? (A1 vs A2)
Are variances adeguately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test
-2*log(Likelihood Ratio) Test df
p-value
Test
Test
Test
Test
16.4116
0.698622
0.698622
0.601705
0.01171
0.8735
0.8735
0.4379
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is greater than .1.
model appears to be appropriate here
A homogeneous variance
The p-value for Test 3 is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4 is greater than .1. The model chosen seems
to adeguately describe the data
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Benchmark Dose Computation
Specified effect
1
Risk Type
Estimated standard deviations from the control mean
Confidence level
0. 95
BMD
0.0834788
BMDL
0. 0158129
Increased Length of General Path in Morris Water Maze
The procedure outlined above was applied to the data on increased length of general path
in Morris water maze from the neurodevelopmental study by He et al. (2008) (see Table C-l).
Table C-3 summarizes the BMD modeling results. The constant variance model did not provide
adequate fit to the variance data; however, variance was modeled adequately using the
nonconstant variance model in BMDS. With the nonconstant variance model applied, only the
Exponential models (all) and the Power model provided adequate fit to the means. While the
Hill model provided an apparent fit to the means, this model did not return a BMDL estimate.
The BMDLs for models providing adequate fit varied by greater than threefold, so the model
with the lowest BMDL (Exponential Models 4 and 5) was selected. The BMD and BMDL from
this model were 2.46 and 0.70 mg La/kg-day, respectively. Figure C-2 shows the fit of the
Exponential Model 4 to the data; the textual BMD output for this model follows the figure.
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Table C-3. BMD Model Predictions for Increased General Path Distance in Morris Water Maze in Male Rats Exposed to
Lanthanum Chloride from GD 0 through 6 Months of Agea
Model
Variance
/>-Valucb
Mean
/>-Valucb
Scaled Residual:
Dose Nearest the BMDC
AIC
BMDisd
(mg/kg-d)
BMDLisd
(mg/kg-d)
Constant variance
Exponential (Model 2)d
0.055
0.1895
-0.038
666.82
20.88
15.43
Exponential (Model 3)d
0.055
0.1895
-0.038
666.82
20.88
15.43
Exponential (Model 4)d
0.055
0.4598
-0.057
666.04
2.32
0.73
Exponential (Model 5)d
0.055
0.4598
-0.057
666.04
2.32
0.73
Hilld
0.055
0.4838
-0.095
665.99
3.06
0.33
Linear6
0.055
0.1985
-0.056
666.73
20.26
13.84
Polynomial (2-degree)6
0.055
0.1985
-0.056
666.73
20.26
13.84
Polynomial (3-degree)6
0.055
0.1985
-0.056
666.73
20.26
13.84
Power6
0.055
0.1985
-0.056
666.73
20.26
13.84
Nonconstant variance
Exponential (Model 2)d
0.235
0.1327
-0.064
664.84
18.38
12.63
Exponential (Model 3)d
0.235
0.1327
-0.064
664.84
18.38
12.63
Exponential (Model 4)e f
0.235
0.1511
0.382
664.87
2.46
0.70
Exponential (Model 5)d
0.235
0.1511
0.382
664.87
2.46
0.70
Hilld
0.235
0.1567
0.336
664.81
2.89
NA
Linear6
0.235
0.1397
-0.091
664.74
17.30
10.76
Polynomial (2-degree)6
0.235
0.1397
-0.091
664.74
17.30
10.76
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Table C-3. BMD Model Predictions for Increased General Path Distance in Morris Water Maze in Male Rats Exposed to
Lanthanum Chloride from GD 0 through 6 Months of Agea
Variance
Mean
Scaled Residual:
BMDisd
BMDLisd
Model
/>-Valucb
/>-Valucb
Dose Nearest the BMDC
AIC
(mg/kg-d)
(mg/kg-d)
Polynomial (3-degree)6
0.235
0.1397
-0.091
664.74
17.30
10.76
Power"1
0.235
0.1397
-0.091
664.74
17.30
10.76
aHe et al. (2008).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
°Scaled residuals at doses immediately below and above the BMD; also, the largest residual at any dose.
dPower restricted to >1.
"Coefficients restricted to be positive.
Selected model. Constant variance model did not fit variance data, but the model variance model did. With nonhomogeneous variance model applied, the exponential
and power models provided adequate fit to the means. BMDLs for models providing adequate fit were not sufficiently close (differed by >two- to threefold), so the
model with the lowest BMDL was selected (Exponential Model 4; Exponential Model 5 converged onto Model 4).
AIC = Akaike's information criterion; BMD = benchmark dose; BMDL = benchmark dose lower confidence limit; GD = gestation day; NA = not applicable (BMDL
computation failed or the BMD was higher than the highest dose tested) or there is no scaled residual at the dose below the BMD because the BMD value is the lowest
dose tested (0 mg/kg-d-control); SD = standard deviation.
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Exponential 4 Model, with BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
dose
Figure C-2. Fit of the Exponential Model 4 to Data on Length of General Path in Morris
Water Maze in Male Rats Exposed to Lanthanum Chloride from GD 0 to 6 Months of Age
(He et al.. 2008)
Text Output for Figure C-2:
Exponential Model. (Version: 1.10; Date: 01/12/2015)
Input Data File:
C:/Users/j zhao/BMDS2 601/Data/exp_UntitledData2_Exp-ModelVariance-BMRlStd-Up.(d)
Gnuplot Plotting File:
Thu Jan 25 15:27:31 2018
BMDS Model Run
The form of the response function by Model:
Model 2
Model 3
Model 4
Model 5
Y[dose] = a * exp{sign * b * dose}
Y[dose] = a * exp{sign * (b * dose)Ad}
Y[dose] = a * [c-(c-l) * exp{-b * dose}]
Y[dose] = a * [c-(c-l) * exp{-(b * dose)Ad}]
Note: Y[dose] is the median response for exposure
sign = +1 for increasing trend in data;
sign = -1 for decreasing trend.
Model 2 is nested within Models 3 and 4.
Model 3 is nested within Model 5.
Model 4 is nested within Model 5.
dose;
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Dependent variable = Mean
Independent variable = Dose
Data are assumed to be distributed: normally
Variance Model: exp(lnalpha +rho *ln(Y[dose]))
The variance is to be modeled as Var(i) = exp(lalpha + log(mean(i)) * rho)
Total number of dose groups = 4
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
MLE solution provided: Exact
Initial Parameter Values
Variable Model 4
lnalpha 0.209421
rho 1.64514
a 265.05
b 0.102201
c 1.95303
d 1 Specified
Parameter Estimates
Variable Model 4
lnalpha
rho
a
b
c
0.91838
1.52673
303.181
0.404591
1.65021
Std. Err.
5.61445
0.951704
24.6196
0.332096
0.202799
Table of Stats From Input Data
Dose
0
0.06
1
23
15
15
15
15
Obs Mean
279
325
383
493
Obs Std Dev
112
157
112
202
Dose
0
0.06
1
23
Estimated Values of Interest
Est Mean Est Std Scaled Residual
303.2
307. 9
368.8
500.3
124.1
125 . 6
144.1
181.9
-0.7545
0.527
0.3822
-0.1553
Other models for which likelihoods are calculated:
Model A1: Yij = Mu(i) + e(ij)
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Var{e(ij)} = SigmaA2
Model A2: Yij
Var{e(ij)}
Model A3: Yij
Var{e(ij)}
Model R: Yij
Var{e(ij)}
Mu(i) + e(i j)
Sigma(i)A2
Mu(i) + e(i j)
exp(lalpha + log(mean(i)) * rho)
Mu + e(i)
SigmaA2
Model
A1
A2
A3
R
4
Likelihoods of Interest
Log (likelihood) DF
-328.7481 5
-324.9529 8
-326.4027 6
-336.6879 2
-327.4334 5
AIC
667.4962
665.9058
664.8055
677.3759
664.8667
Additive constant for all log-likelihoods = -55.14. This constant added to the
above values gives the log-likelihood including the term that does not
depend on the model parameters.
Explanation of Tests
Does response and/or variances differ among Dose levels? (A2 vs. R)
Are Variances Homogeneous? (A2 vs. Al)
Are variances adeguately modeled? (A2 vs. A3)
Test 6a: Does Model 4 fit the data? (A3 vs 4)
Test
1:
Test
2 :
Test
3:
Test
Test 1
Test 2
Test 3
Test 6a
Tests of Interest
-2*log(Likelihood Ratio)
23. 47
7.59
2.9
2.061
D. F.
6
3
2
1
p-value
0.0006534
0.05528
0.2346
0.1511
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose
levels, it seems appropriate to model the data.
The p-value for Test 2 is less than .1. A non-homogeneous
variance model appears to be appropriate.
The p-value for Test 3 is greater than .1. The modeled
variance appears to be appropriate here.
The p-value for Test 6a is greater than .1. Model 4 seems
to adeguately describe the data.
Benchmark Dose Computations:
Specified Effect = 1.000000
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Risk Type = Estimated standard deviations from control
Confidence Level = 0.950000
BMD = 2.45522
BMDL = 0.69732 8
Decreased Preference for Target Quadrant in Morris Water Maze
The procedure outlined above was applied to the data on decreased preference for target
quadrant in the Morris water maze from the neurodevelopmental study by He et al. (2008)
(see Table C-l). Table C-4 summarizes the BMD modeling results. The constant variance
model provided adequate fit to the variance data. With the constant variance model applied, only
Exponential Models 4 and 5 provided adequate fit to the means. The BMDLs from these models
only differed by less than twofold, which would typically lead to selection of the model with the
lowest AIC. However, the AICs (as well as scaled residuals) were identical for both models.
Exponential Model 4 was selected because it is more parsimonious (i.e., has fewer parameters).
The BMD and BMDL from this model were 0.93 and 0.11 mg La/kg-day, respectively.
Figure C-3 shows the fit of the Exponential Model 4 to the data; the textual BMD output for this
model follows the figure.
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Table C-4. BMD Model Predictions for Target Quadrant Preference in Morris Water Maze in Male Rats Exposed to Lanthanum
Chloride from GD 0 through 6 Months of Agea
Model
Variance
/>-Valucb
Mean
/>-Valucb
Scaled Residual:
Dose nearest BMDC
AIC
BMDisd
(mg/kg-d)
BMDLisd
(mg/kg-d)
Constant variance
Exponential (Model 2)d
0.7344
0.01671
0.116
282.14
23.20
14.39
Exponential (Model 3)d
0.7344
0.01671
0.116
282.14
23.20
14.39
Exponential (Model 4)d'e
0.7344
0.8539
0.030
275.99
0.93
0.11
Exponential (Model 5)d
0.7344
0.8539
0.030
275.99
0.93
0.06
Hilld
0.7344
NA
0.000
277.96
0.82
0.07
Lineal
0.7344
0.01613
0.097
282.21
23.39
15.30
Polynomial (2-degree/
0.7344
0.01613
0.097
282.21
23.39
15.30
Polynomial (3-degree/
0.7344
0.01613
0.097
282.21
23.39
15.30
Power"1
0.7344
0.01613
0.097
282.21
23.39
15.30
•'11c ct al. (2008).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
°Scaled residuals at doses immediately below and above the BMD; also the largest residual at any dose.
dPower restricted to >1.
"Selected model. Constant variance model provided adequate fit to variance data. With constant variance applied, only Exponential Models 4 and 5 provided adequate
fit to the means. The BMDLs for these two models are sufficiently close (differ by
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Exponential 4 Model, with BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
dose
Figure C-3. Fit of the Exponential Model 4 to Data on Decreased Preference for Target
Quadrant in Morris Water Maze in Male Rats Exposed to Lanthanum Chloride from
GD 0 to 6 Months of Age (He et al., 2008)
Text Output for Figure C-3:
Exponential Model. (Version: 1.10; Date: 01/12/2015)
Input Data File:
C:/Users/j zhao/BMDS2 601/Data/exp_UntitledData3_Exp-ConstantVariance-BMRlStd-Down. (d)
Gnuplot Plotting File:
Thu Jan 25 15:46:57 2018
BMDS Model Run
The form of the response function by Model:
Model 2
Model 3
Model 4
Model 5
Y[dose] = a * exp{sign * b * dose}
Y[dose] = a * exp{sign * (b * dosej^d}
Y[dose] = a * [c-(c-l) * exp{-b * dose}]
Y[dose] = a * [c-(c-l) * exp{-(b * dose)Ad}]
Note: Y[dose] is the median response for exposure
sign = +1 for increasing trend in data;
sign = -1 for decreasing trend.
Model 2 is nested within Models 3 and 4.
Model 3 is nested within Model 5.
Model 4 is nested within Model 5.
dose;
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Dependent variable = Mean
Independent variable = Dose
Data are assumed to be distributed: normally
Variance Model: exp(lnalpha +rho *ln(Y[dose]))
rho is set to 0.
A constant variance model is fit.
Total number of dose groups = 4
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
MLE solution provided: Exact
Initial Parameter Values
Variable Model 4
lnalpha 3.4 65 93
rho 0 Specified
a 37.8
b 0.0944057
c 0.705467
d 1 Specified
Parameter Estimates
Variable Model 4 Std. Err.
lnalpha 3.4665 5.84684
a 35.8268 1.12
b 1.39365 0.978065
c 0.782024 0.0464124
Table of Stats From Input Data
Dose N Obs Mean Obs Std Dev
0 15 36 5.8
0.06 15 35 5
1 15 30 6.7
23 15 28 5.8
Estimated Values of Interest
Dose Est Mean Est Std Scaled Residual
0 35.83 5.659 0.1185
0.06 35.2 5.659 -0.1371
1 29.96 5.659 0.03049
23 28.02 5.659 -0.01192
Other models for which likelihoods are calculated:
Model A1: Yij = Mu(i) + e(ij)
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Var{e(ij)} = SigmaA2
Model A2: Yij
Var{e(ij)}
Model A3: Yij
Var{e(ij)}
Model R: Yij
Var{e(ij)}
Mu(i) + e(i j)
Sigma(i)A2
Mu(i) + e(i j)
exp(lalpha + log(mean(i)) * rho)
Mu + e(i)
SigmaA2
Likelihoods of Interest
Model
A1
A2
A3
R
4
Log(likelihood) DF
-133.978 5
-133.3391 8
-133.978 5
-142.9709 2
-133.995 4
AIC
277.956
282.6783
277.956
289.9419
275.99
Additive constant for all log-likelihoods = -55.14. This constant added to the
above values gives the log-likelihood including the term that does not
depend on the model parameters.
Explanation of Tests
Does response and/or variances differ among Dose levels? (A2 vs. R)
Are Variances Homogeneous? (A2 vs. Al)
Are variances adeguately modeled? (A2 vs. A3)
Test 6a: Does Model 4 fit the data? (A3 vs 4)
Test
1:
Test
2 :
Test
3:
Test
Test 1
Test 2
Test 3
Test 6a
Tests of Interest
-2*log(Likelihood Ratio)
19.26
1.278
1.278
0.03393
D. F.
6
3
3
1
p-value
0. 003741
0.7344
0.7344
0. 8539
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose
levels, it seems appropriate to model the data.
The p-value for Test 2 is greater than .1. A homogeneous
variance model appears to be appropriate here.
The p-value for Test 3 is greater than .1. The modeled
variance appears to be appropriate here.
The p-value for Test 6a is greater than .1. Model 4 seems
to adeguately describe the data.
Benchmark Dose Computations:
Specified Effect = 1.000000
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Risk Type = Estimated standard deviations from control
Confidence Level = 0.950000
BMD = 0.925403
BMDL = 0.112 065
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