Abstract

Experimental toxicology studies for the purposes of setting occupational exposure limits for aerosols have drawbacks including excessive time and cost which could be overcome or limited by the development of computational approaches. A quantitative, analytical relationship between the characteristics of emerging nanomaterials and related in vivo toxicity can be utilized to better assist in the subsequent mitigation of exposure toxicity by design. Predictive toxicity models can be used to categorize and define exposure limitations for emerging nanomaterials. Model-based no-observed-adverse-effect-level (NOAEL) predictions were derived for toxicologically distinct nanomaterial clusters, referred to as model-predicted no observed adverse effect levels (MP-NOAELs). The lowest range of MP-NOAELs for the polymorphonuclear neutrophil (PMN) response observed by carbon nanotubes (CNTs) was found to be 21–35 μg/kg (cluster “A”), indicating that the CNT belonging to cluster A showed the earliest signs of adverse effects. Only 25% of the MP-NOAEL values for the CNTs can be quantitatively defined at present. The lowest observed MP-NOAEL range for the metal oxide nanoparticles was Cobalt oxide nanoparticles (cluster III) for the macrophage (MAC) response at 54–189 μg/kg. Nearly 50% of the derived MP-NOAEL values for the metal oxide nanoparticles can be quantitatively defined based on current data. A sensitivity analysis of the MP-NOAEL derivation highlighted the dependency of the process on the shape and type of the fitted dose-response model, its parameters, dose selection and spacing, and the sample size analyzed.

References

1.
NIOSH
,
2011
,
Occupational Exposure to Titanium Dioxide
,
National Institute for Occupational Safety and Health
, Washington, DC.
2.
NIOSH
,
2013
,
Occupational Exposure to Carbon Nanotubes and Nanofibers
,
National Institute for Occupational Safety and Health
, Washington, DC.
3.
Yassin
,
A.
,
Yebesi
,
F.
, and
Tingle
,
R.
,
2005
, “
Occupational Exposure to Crystalline Silica Dust in the United States, 1988–2003
,”
Environ. Health Persp.
,
113
(
3
), pp.
255
260
.10.1289/ehp.7384
4.
Dorato
,
M. A.
, and
Engelhardt
,
J. A.
,
2005
, “
The No-Observed-Adverse-Effect-Level in Drug Safety Evaluations: Use, Issues, and Definition(s)
,”
Regul. Toxicol. Pharmacol. RTP
,
42
(
3
), pp.
265
274
.10.1016/j.yrtph.2005.05.004
5.
Nakanishi
,
J.
,
Morimoto
,
Y.
,
Ogura
,
I.
,
Kobayashi
,
N.
,
Naya
,
M.
,
Ema
,
M.
,
Endoh
,
S.
,
Shimada
,
M.
,
Ogami
,
A.
,
Myojyo
,
T.
,
Oyabu
,
T.
,
Gamo
,
M.
,
Kishimoto
,
A.
,
Igarashi
,
T.
, and
Hanai
,
S.
,
2015
, “
Risk Assessment of the Carbon Nanotube Group
,”
Risk Anal.
,
35
(
10
), pp.
1940
1956
.10.1111/risa.12394
6.
Puzyn
,
T.
,
Rasulev
,
B.
,
Gajewicz
,
A.
,
Hu
,
X. K.
,
Dasari
,
T. P.
,
Michalkova
,
A.
,
Hwang
,
H. M.
,
Toropov
,
A.
,
Leszczynska
,
D.
, and
Leszczynski
,
J.
,
2011
, “
Using nano-QSAR to Predict the Cytotoxicity of Metal Oxide Nanoparticles
,”
Nat. Nanotechnol.
,
6
(
3
), pp.
175
178
.10.1038/nnano.2011.10
7.
Burello
,
E.
, and
Worth
,
A. P.
,
2011
, “
QSAR Modeling of Nanomaterials
,”
Wires Nanomed. Nanobiotechnol.
,
3
(
3
), pp.
298
306
.10.1002/wnan.137
8.
Fourches
,
D.
,
Pu
,
D. Q. Y.
,
Tassa
,
C.
,
Weissleder
,
R.
,
Shaw
,
S. Y.
,
Mumper
,
R. J.
, and
Tropsha
,
A.
,
2010
, “
Quantitative Nanostructure-Activity Relationship Modeling
,”
ACS Nano
,
4
(
10
), pp.
5703
5712
.10.1021/nn1013484
9.
Fourches
,
D.
,
Pu
,
D. Q. Y.
, and
Tropsha
,
A.
,
2011
, “
Exploring Quantitative Nanostructure-Activity Relationships (QNAR) Modeling as a Tool for Predicting Biological Effects of Manufactured Nanoparticles
,”
Comb. Chem. High Throughput Screening
,
14
(
3
), pp.
217
225
.10.2174/138620711794728743
10.
Gernand
,
J. M.
, and
Casman
,
E. A.
,
2014
, “
Machine Learning for Nanomaterial Toxicity Risk Assessment
,”
IEEE Intell. Syst.
,
29
(
3
), pp.
84
88
.10.1109/MIS.2014.48
11.
Gernand
,
J. M.
, and
Casman
,
E. A.
,
2014
, “
A Meta-Analysis of Carbon Nanotube Pulmonary Toxicity Studies-How Physical Dimensions and Impurities Affect the Toxicity of Carbon Nanotubes
,”
Risk Anal.
,
34
(
3
), pp.
583
597
.10.1111/risa.12109
12.
Schulte
,
P. A.
,
Leso
,
V.
,
Niang
,
M.
, and
Iavicoli
,
I.
,
2019
, “
Current State of Knowledge on the Health Effects of Engineered Nanomaterials in Workers: A Systematic Review of Human Studies and Epidemiological Investigations
,”
Scand. J. Work, Environ. Health
,
45
(
3
), pp.
217
238
.10.5271/sjweh.3800
13.
Roco
,
M. C.
,
2011
, “
The Long View of Nanotechnology Development: The National Nanotechnology Initiative at 10 Years
,”
J. Nanopart. Res.
,
13
(
2
), pp.
427
445
.10.1007/s11051-010-0192-z
14.
Ramchandran
,
V.
, and
Gernand
,
J. M.
,
2019
, “
A Dose-Response-Recovery Clustering Algorithm for Categorizing Carbon Nanotube Variants Into Toxicologically Distinct Groups
,”
Comput. Toxicol.
,
11
, pp.
25
32
.10.1016/j.comtox.2019.02.003
15.
Drobne
,
D.
,
Jemec
,
A.
, and
Tkalec
,
Z. P.
,
2009
, “
In Vivo Screening to Determine Hazards of Nanoparticles: Nanosized TiO2
,”
Environ. Pollut.
,
157
(
4
), pp.
1157
1164
.10.1016/j.envpol.2008.10.018
16.
Choi
,
J. Y.
,
Ramachandran
,
G.
, and
Kandlikar
,
M.
,
2009
, “
The Impact of Toxicity Testing Costs on Nanomaterial Regulation
,”
Environ. Sci. Technol.
,
43
(
9
), pp.
3030
3034
.10.1021/es802388s
17.
MacPhail
,
R. C.
,
Grulke
,
E. A.
, and
Yokel
,
R. A.
,
2013
, “
Assessing Nanoparticle Risk Poses Prodigious Challenges
,”
Wires Nanomed. Nanobiotechnol.
,
5
(
4
), pp.
374
387
.10.1002/wnan.1216
18.
Xing
,
B.
,
Vecitis
,
C. D.
,
Senesi
,
N.
,
Aschberger
,
K.
,
Christensen
,
F. M.
,
Rasmussen
,
K.
, and
Jensen
,
K. A.
,
2016
,
Feasibility and Challenges of Human Health Risk Assessment for Engineered Nanomaterials
,
Engineered Nanoparticles and the Environment
: Biophysicochemical Processes and Toxicity, B. Xing, C. D. Vecitis and N. Senesi, eds.10.1002/9781119275855.ch21
19.
Haber
,
L. T.
,
Dourson
,
M. L.
,
Allen
,
B. C.
,
Hertzberg
,
R. C.
,
Parker
,
A.
,
Vincent
,
M. J.
,
Maier
,
A.
, and
Boobis
,
A. R.
,
2018
, “
Benchmark Dose (BMD) Modeling: Current Practice, Issues, and Challenges
,”
Crit. Rev. Toxicol.
,
48
(
5
), pp.
387
415
.10.1080/10408444.2018.1430121
20.
Filipsson
,
A. F.
,
Sand
,
S.
,
Nilsson
,
J.
, and
Victorin
,
K.
,
2003
, “
The Benchmark Dose method - Review of Available Models, and Recommendations for Application in Health Risk Assessment
,”
Crit. Rev. Toxicol.
,
33
(
5
), pp.
505
542
.10.1080/748638748
21.
Starr
,
T. B.
,
Goodman
,
J. I.
, and
Hoel
,
D. G.
,
2005
, “
Uses of Benchmark Dose Methodology in Quantitative Risk Assessment
,”
Regul. Toxicol. Pharm.
,
42
(
1
), pp.
1
2
.10.1016/j.yrtph.2005.01.007
22.
Setzer
,
R. W.
, and
Kimmel
,
C. A.
,
2003
, “
Use of NOAEL, Benchmark Dose, and Other Models for Human Risk Assessment of Hormonally Active Substances
,”
Pure Appl. Chem.
,
75
(
11–12
), pp.
2151
2158
.10.1351/pac200375112151
23.
Davis
,
J. A.
,
Gift
,
J. S.
, and
Zhao
,
Q. J.
,
2011
, “
Introduction to Benchmark Dose Methods and U.S. EPA's Benchmark Dose Software (BMDS) Version 2.1.1
,”
Toxicol. Appl. Pharmacol.
,
254
(
2
), pp.
181
191
.10.1016/j.taap.2010.10.016
24.
Pauluhn
,
J.
,
2010
, “
Subchronic 13-Week Inhalation Exposure of Rats to Multiwalled Carbon Nanotubes: Toxic Effects Are Determined by Density of Agglomerate Structures, Not Fibrillar Structures
,”
Toxicol. Sci.
,
113
(
1
), pp.
226
242
.10.1093/toxsci/kfp247
25.
Ma-Hock
,
L.
,
Treumann
,
S.
,
Strauss
,
V.
,
Brill
,
S.
,
Luizi
,
F.
,
Mertler
,
M.
,
Wiench
,
K.
,
Gamer
,
A. O.
,
van Ravenzwaay
,
B.
, and
Landsiedel
,
R.
,
2009
, “
Inhalation Toxicity of Multiwall Carbon Nanotubes in Rats Exposed for 3 Months
,”
Toxicol. Sci.
,
112
(
2
), pp.
468
481
.10.1093/toxsci/kfp146
26.
Muller
,
J.
,
Huaux
,
F.
,
Moreau
,
N.
,
Misson
,
P.
,
Heilier
,
J. F.
,
Delos
,
M.
,
Arras
,
M.
,
Fonseca
,
A.
,
Nagy
,
J. B.
, and
Lison
,
D.
,
2005
, “
Respiratory Toxicity of Multi-Wall Carbon Nanotubes
,”
Toxicol. Appl. Pharm.
,
207
(
3
), pp.
221
231
.10.1016/j.taap.2005.01.008
27.
Shvedova
,
A. A.
,
Kisin
,
E.
,
Murray
,
A. R.
,
Johnson
,
V. J.
,
Gorelik
,
O.
,
Arepalli
,
S.
,
Hubbs
,
A. F.
,
Mercer
,
R. R.
,
Keohavong
,
P.
,
Sussman
,
N.
,
Jin
,
J.
,
Yin
,
J.
,
Stone
,
S.
,
Chen
,
B. T.
,
Deye
,
G.
,
Maynard
,
A.
,
Castranova
,
V.
,
Baron
,
P. A.
, and
Kagan
,
V. E.
,
2008
, “
Inhalation vs. aspiration of Single-Walled Carbon Nanotubes in C57BL/6 Mice: Inflammation, Fibrosis, Oxidative Stress, and Mutagenesis
,”
Am. J. Physiol. Lung C
,
295
(
4
), pp.
L552
L565
.10.1152/ajplung.90287.2008
28.
Nygaard
,
U. C.
,
Hansen
,
J. S.
,
Samuelsen
,
M.
,
Alberg
,
T.
,
Marioara
,
C. D.
, and
Lovik
,
M.
,
2009
, “
Single-Walled and Multi-Walled Carbon Nanotubes Promote Allergic Immune Responses in Mice
,”
Toxicol. Sci.
,
109
(
1
), pp.
113
123
.10.1093/toxsci/kfp057
29.
Warheit
,
D. B.
,
Laurence
,
B. R.
,
Reed
,
K. L.
,
Roach
,
D. H.
,
Reynolds
,
G. A. M.
, and
Webb
,
T. R.
,
2003
, “
Comparative Pulmonary Toxicity Assessment of Single-Wall Carbon Nanotubes in Rats
,”
Toxicol. Sci.
,
77
(
1
), pp.
117
125
.10.1093/toxsci/kfg228
30.
Park
,
E. J.
,
Roh
,
J.
,
Kim
,
S. N.
,
Kang
,
M. S.
,
Han
,
Y. A.
,
Kim
,
Y.
,
Hong
,
J. T.
, and
Choi
,
K.
,
2011
, “
A Single Intratracheal Instillation of Single-Walled Carbon Nanotubes Induced Early Lung Fibrosis and Subchronic Tissue Damage in Mice
,”
Arch. Toxicol.
,
85
(
9
), pp.
1121
1131
.10.1007/s00204-011-0655-8
31.
Teeguarden
,
J. G.
,
Webb-Robertson
,
B. J.
,
Waters
,
K. M.
,
Murray
,
A. R.
,
Kisin
,
E. R.
,
Varnum
,
S. M.
,
Jacobs
,
J. M.
,
Pounds
,
J. G.
,
Zanger
,
R. C.
, and
Shvedova
,
A. A.
,
2011
, “
Comparative Proteomics and Pulmonary Toxicity of Instilled Single-Walled Carbon Nanotubes, Crocidolite Asbestos, and Ultrafine Carbon Black in Mice
,”
Toxicol. Sci.
,
120
(
1
), pp.
123
135
.10.1093/toxsci/kfq363
32.
Elgrabli
,
D.
,
Abella-Gallart
,
S.
,
Robidel
,
F.
,
Rogerieux
,
F.
,
Boczkowski
,
J.
, and
Lacroix
,
G.
,
2008
, “
Induction of Apoptosis and Absence of Inflammation in Rat Lung After Intratracheal Instillation of Multiwalled Carbon Nanotubes
,”
Toxicology
,
253
(
1–3
), pp.
131
136
.10.1016/j.tox.2008.09.004
33.
Mercer
,
R. R.
,
Scabilloni
,
J.
,
Wang
,
L.
,
Kisin
,
E.
,
Murray
,
A. R.
,
Schwegler-Berry
,
D.
,
Shvedova
,
A. A.
, and
Castranova
,
V.
,
2008
, “
Alteration of Deposition Pattern and Pulmonary Response as a Result of Improved Dispersion of Aspirated Single-Walled Carbon Nanotubes in a Mouse Model
,”
Am. J. Physiol. Lung C
,
294
(
1
), pp.
L87
L97
.10.1152/ajplung.00186.2007
34.
Porter
,
D. W.
,
Hubbs
,
A. F.
,
Mercer
,
R. R.
,
Wu
,
N. Q.
,
Wolfarth
,
M. G.
,
Sriram
,
K.
,
Leonard
,
S.
,
Battelli
,
L.
,
Schwegler-Berry
,
D.
,
Friend
,
S.
,
Andrew
,
M.
,
Chen
,
B. T.
,
Tsuruoka
,
S.
,
Endo
,
M.
, and
Castranova
,
V.
,
2010
, “
Mouse Pulmonary Dose- and Time Course-Responses Induced by Exposure to Multi-Walled Carbon Nanotubes
,”
Toxicology
,
269
(
2–3
), pp.
136
147
.10.1016/j.tox.2009.10.017
35.
Ellinger-Ziegelbauer
,
H.
, and
Pauluhn
,
J.
,
2009
, “
Pulmonary Toxicity of Multi-Walled Carbon Nanotubes (Baytubes (R)) Relative to Alpha-Quartz Following a Single 6 h Inhalation Exposure of Rats and a 3 Months Post-Exposure Period
,”
Toxicology
,
266
(
1–3
), pp.
16
29
.10.1016/j.tox.2009.10.007
36.
Shvedova
,
A. A.
,
Kisin
,
E. R.
,
Mercer
,
R.
,
Murray
,
A. R.
,
Johnson
,
V. J.
,
Potapovich
,
A. I.
,
Tyurina
,
Y. Y.
,
Gorelik
,
O.
,
Arepalli
,
S.
,
Schwegler-Berry
,
D.
,
Hubbs
,
A. F.
,
Antonini
,
J.
,
Evans
,
D. E.
,
Ku
,
B. K.
,
Ramsey
,
D.
,
Maynard
,
A.
,
Kagan
,
V. E.
,
Castranova
,
V.
, and
Baron
,
P.
,
2005
, “
Unusual Inflammatory and Fibrogenic Pulmonary Responses to Single-Walled Carbon Nanotubes in Mice
,”
Am. Journal Physiol. Lung Cell. Mol. Physiol.
,
289
(
5
), pp.
L698
708
.10.1152/ajplung.00084.2005
37.
Ge
,
C. C.
,
Meng
,
L.
,
Xu
,
L. G.
,
Bai
,
R.
,
Du
,
J. F.
,
Zhang
,
L. L.
,
Li
,
Y.
,
Chang
,
Y. Z.
,
Zhao
,
Y. L.
, and
Chen
,
C. Y.
,
2012
, “
Acute Pulmonary and Moderate Cardiovascular Responses of Spontaneously Hypertensive Rats After Exposure to Single-Wall Carbon Nanotubes
,”
Nanotoxicology
,
6
(
5
), pp.
526
542
.10.3109/17435390.2011.587905
38.
Nemmar
,
A.
,
Melghit
,
K.
, and
Ali
,
B. H.
,
2008
, “
The Acute Proinflammatory and Prothrombotic Effects of Pulmonary Exposure to Rutile TiO2 Nanorods in Rats
,”
Exp. Biol. Med. (Maywood)
,
233
(
5
), pp.
610
619
.10.3181/0706-RM-165
39.
Oberdorster
,
G.
,
Ferin
,
J.
,
Gelein
,
R.
,
Soderholm
,
S. C.
, and
Finkelstein
,
J.
,
1992
, “
Role of the Alveolar Macrophage in Lung Injury: Studies With Ultrafine Particles
,”
Environ. Health Perspect.
,
97
, pp.
193
199
.10.2307/3431353
40.
Warheit
,
D. B.
,
Webb
,
T. R.
,
Sayes
,
C. M.
,
Colvin
,
V. L.
, and
Reed
,
K. L.
,
2006
, “
Pulmonary Instillation Studies With Nanoscale TiO2 Rods and Dots in Rats: Toxicity is Not Dependent Upon Particle Size and Surface Area
,”
Toxicol. Sci.
,
91
(
1
), pp.
227
236
.10.1093/toxsci/kfj140
41.
Renwick
,
L. C.
,
Brown
,
D.
,
Clouter
,
A.
, and
Donaldson
,
K.
,
2004
, “
Increased Inflammation and Altered Macrophage Chemotactic Responses Caused by Two Ultrafine Particle Types
,”
Occup. Environ. Med.
,
61
(
5
), pp.
442
447
.10.1136/oem.2003.008227
42.
Rehn
,
B.
,
Seiler
,
F.
,
Rehn
,
S.
,
Bruch
,
J.
, and
Maier
,
M.
,
2003
, “
Investigations on the Inflammatory and Genotoxic Lung Effects of Two Types of Titanium Dioxide: Untreated and Surface Treated
,”
Toxicol. Appl. Pharm.
,
189
(
2
), pp.
84
95
.10.1016/S0041-008X(03)00092-9
43.
Grassian
,
V. H.
,
Adamcakova-Dodd
,
A.
,
Pettibone
,
J. M.
,
O'Shaughnessy
,
P. T.
, and
Thorne
,
P. S.
,
2007
, “
Inflammatory Response of Mice to Manufactured Titanium Dioxide Nanoparticles: Comparison of Size Effects Through Different Exposure Routes
,”
Nanotoxicology
,
1
(
3
), pp.
211
226
.10.1080/17435390701694295
44.
Warheit
,
D. B.
,
Webb
,
T. R.
,
Reed
,
K. L.
,
Frerichs
,
S.
, and
Sayes
,
C. M.
,
2007
, “
Pulmonary Toxicity Study in Rats With Three Forms of ultrafine-TiO2 Particles: Differential Responses Related to Surface Properties
,”
Toxicology
,
230
(
1
), pp.
90
104
.10.1016/j.tox.2006.11.002
45.
Warheit
,
D. B.
,
Sayes
,
C. M.
,
Frame
,
S. R.
, and
Reed
,
K. L.
,
2010
, “
Pulmonary Exposures to Sepiolite Nanoclay Particulates in Rats: Resolution Following Multinucleate Giant Cell Formation
,”
Toxicol. Lett.
,
192
(
3
), pp.
286
293
.10.1016/j.toxlet.2009.11.006
46.
Kobayashi
,
N.
,
Naya
,
M.
,
Endoh
,
S.
,
Maru
,
J.
,
Yamamoto
,
K.
, and
Nakanishi
,
J.
,
2009
, “
Comparative Pulmonary Toxicity Study of Nano-TiO2 Particles of Different Sizes and Agglomerations in Rats: Different Short- and Long-Term Post-Instillation Results
,”
Toxicology
,
264
(
1–2
), pp.
110
118
.10.1016/j.tox.2009.08.002
47.
Gustafsson
,
A.
,
Lindstedt
,
E.
,
Elfsmark
,
L. S.
, and
Bucht
,
A.
,
2011
, “
Lung Exposure of Titanium Dioxide Nanoparticles Induces Innate Immune Activation and Long-Lasting Lymphocyte Response in the Dark Agouti Rat
,”
J. Immunotoxicol.
,
8
(
2
), pp.
111
121
.10.3109/1547691X.2010.546382
48.
Oyabu
,
T.
,
Morimoto
,
Y.
,
Hirohashi
,
M.
,
Horie
,
M.
,
Kambara
,
T.
,
Lee
,
B. W.
,
Hashiba
,
M.
,
Mizuguchi
,
Y.
,
Myojo
,
T.
, and
Kuroda
,
E.
,
2013
, “
Dose-Dependent Pulmonary Response of Well-Dispersed Titanium Dioxide Nanoparticles Following Intratracheal Instillation
,”
J. Nanopart. Res.
,
15
(
4
), p.10.1007/s11051-013-1600-y
49.
Roberts
,
J. R.
,
Chapman
,
R. S.
,
Tirumala
,
V. R.
,
Karim
,
A.
,
Chen
,
B. T.
,
Schwegler-Berry
,
D.
,
Stefaniak
,
A. B.
,
Leonard
,
S. S.
, and
Antonini
,
J. M.
,
2011
, “
Toxicological Evaluation of Lung Responses After Intratracheal Exposure to Non-Dispersed Titanium Dioxide Nanorods
,”
J. Toxicol. Environ. Health A
,
74
(
12
), pp.
790
810
.10.1080/15287394.2011.567954
50.
Silva
,
R. M.
,
TeeSy
,
C.
,
Franzi
,
L.
,
Weir
,
A.
,
Westerhoff
,
P.
,
Evans
,
J. E.
, and
Pinkerton
,
K. E.
,
2013
, “
Biological Response to Nano-Scale Titanium Dioxide (Tio2): Role of Particle Dose, Shape, and Retention
,”
J. Toxicol. Environ. Health A
,
76
(
16
), pp.
953
972
.10.1080/15287394.2013.826567
51.
Gosens
,
I.
,
Post
,
J. A.
,
de la Fonteyne
,
L. J. J.
,
Jansen
,
E. H. J. M.
,
Geus
,
J. W.
,
Cassee
,
F. R.
, and
de Jong
,
W. H.
,
2010
, “
Impact of Agglomeration State of Nano- and Submicron Sized Gold Particles on Pulmonary Inflammation
,”
Part Fibre Toxicol.
,
7
(
1
), p.
37
.10.1186/1743-8977-7-37
52.
Cho
,
W. S.
,
Choi
,
M.
,
Han
,
B. S.
,
Cho
,
M.
,
Oh
,
J.
,
Park
,
K.
,
Kim
,
S. J.
,
Kim
,
S. H.
, and
Jeong
,
J.
,
2007
, “
Inflammatory Mediators Induced by Intratracheal Instillation of Ultrafine Amorphous Silica Particles
,”
Toxicol. Lett.
,
175
(
1–3
), pp.
24
33
.10.1016/j.toxlet.2007.09.008
53.
Creutzenberg
,
O.
,
Hansen
,
T.
,
Ernst
,
H.
,
Muhle
,
H.
,
Oberdorster
,
G.
, and
Hamilton
,
R.
,
2008
, “
Toxicity of a Quartz With Occluded Surfaces in a 90-Day Intratracheal Instillation Study in Rats
,”
Inhalation Toxicol.
,
20
(
11
), pp.
995
1008
.10.1080/08958370802123903
54.
Roursgaard
,
M.
,
Poulsen
,
S. S.
,
Poulsen
,
L. K.
,
Hammer
,
M.
,
Jensen
,
K. A.
,
Utsunomiya
,
S.
,
Ewing
,
R. C.
,
Balic-Zunic
,
T.
,
Nielsen
,
G. D.
, and
Larsen
,
S. T.
,
2010
, “
Time-Response Relationship of Nano and Micro Particle Induced Lung Inflammation. Quartz as Reference Compound
,”
Hum. Exp. Toxicol.
,
29
(
11
), pp.
915
933
.10.1177/0960327110363329
55.
Morimoto
,
Y.
,
Hirohashi
,
M.
,
Ogami
,
A.
,
Oyabu
,
T.
,
Myojo
,
T.
,
Nishi
,
K.
,
Kadoya
,
C.
,
Todoroki
,
M.
,
Yamamoto
,
M.
,
Murakami
,
M.
,
Shimada
,
M.
,
Wang
,
W. N.
,
Yamamoto
,
K.
,
Fujita
,
K.
,
Endoh
,
S.
,
Uchida
,
K.
,
Shinohara
,
N.
,
Nakanishi
,
J.
, and
Tanaka
,
I.
,
2010
, “
Inflammogenic Effect of Well-Characterized Fullerenes in Inhalation and Intratracheal Instillation Studies
,”
Part. Fibre Toxicol.
,
7
(
1
), p.
4
.10.1186/1743-8977-7-4
56.
Ban
,
M.
,
Langonne
,
I.
,
Huguet
,
N.
, and
Goutet
,
M.
,
2012
, “
Effect of Submicron and Nano-Iron Oxide Particles on Pulmonary Immunity in Mice
,”
Toxicol. Lett.
,
210
(
3
), pp.
267
275
.10.1016/j.toxlet.2012.02.004
57.
Pirela
,
S.
,
Molina
,
R.
,
Watson
,
C.
,
Cohen
,
J. M.
,
Bello
,
D.
,
Demokritou
,
P.
, and
Brain
,
J.
,
2013
, “
Effects of Copy Center Particles on the Lungs: A Toxicological Characterization Using a Balb/c Mouse Model
,”
Inhalation Toxicol.
,
25
(
9
), pp.
498
508
.10.3109/08958378.2013.806614
58.
Zhu
,
M. T.
,
Feng
,
W. Y.
,
Wang
,
B.
,
Wang
,
T. C.
,
Gu
,
Y. Q.
,
Wang
,
M.
,
Wang
,
Y.
,
Ouyang
,
H.
,
Zhao
,
Y. L.
, and
Chai
,
Z. F.
,
2008
, “
Comparative Study of Pulmonary Responses to Nano- and Submicron-Sized Ferric Oxide in Rats
,”
Toxicology
,
247
(
2–3
), pp.
102
111
.10.1016/j.tox.2008.02.011
59.
Katsnelson
,
B.
,
Privalova
,
L. I.
,
Kuzmin
,
S. V.
,
Degtyareva
,
T. D.
,
Sutunkova
,
M. P.
,
Yeremenko
,
O. S.
,
Minigalieva
,
I. A.
,
Kireyeva
,
E. P.
,
Khodos
,
M. Y.
,
Kozitsina
,
A. N.
,
Malakhova
,
N. A.
,
Glazyrina
,
J. A.
,
Shur
,
V. Y.
,
Shishkin
,
E. I.
, and
Nikolaeva
,
E. V.
,
2010
, “
Some Peculiarities of Pulmonary Clearance Mechanisms in Rats After Intratracheal Instillation of Magnetite (Fe3O4) Suspensions With Different Particle Sizes in the Nanometer and Micrometer Ranges: Are We Defenseless Against Nanoparticles?
,”
Int. J. Occup. Environ. Health
,
16
(
4
), pp.
508
524
.10.1179/oeh.2010.16.4.508
60.
Sayes
,
C. M.
,
Reed
,
K. L.
, and
Warheit
,
D. B.
,
2007
, “
Assessing Toxicity of Fine and Nanoparticles: Comparing In Vitro Measurements to In Vivo Pulmonary Toxicity Profiles
,”
Toxicol. Sci.
,
97
(
1
), pp.
163
180
.10.1093/toxsci/kfm018
61.
Toya
,
T.
,
Takata
,
A.
,
Otaki
,
N.
,
Takaya
,
M.
,
Serita
,
F.
,
Yoshida
,
K.
, and
Kohyama
,
N.
,
2010
, “
Pulmonary Toxicity Induced by Intratracheal Instillation of Coarse and Fine Particles of Cerium Dioxide in Male Rats
,”
Ind. Health
,
48
(
1
), pp.
3
11
.10.2486/indhealth.48.3
62.
Morimoto
,
Y.
,
Ogami
,
A.
,
Todoroki
,
M.
,
Yamamoto
,
M.
,
Murakami
,
M.
,
Hirohashi
,
M.
,
Oyabu
,
T.
,
Myojo
,
T.
,
Nishi
,
K. I.
,
Kadoya
,
C.
,
Yamasaki
,
S.
,
Nagatomo
,
H.
,
Fujita
,
K.
,
Endoh
,
S.
,
Uchida
,
K.
,
Yamamoto
,
K.
,
Kobayashi
,
N.
,
Nakanishi
,
J.
, and
Tanaka
,
I.
,
2010
, “
Expression of Inflammation-Related Cytokines Following Intratracheal Instillation of Nickel Oxide Nanoparticles
,”
Nanotoxicology
,
4
(
2
), pp.
161
176
.10.3109/17435390903518479
63.
Xia
,
T. A.
,
Zhao
,
Y.
,
Sager
,
T.
,
George
,
S.
,
Pokhrel
,
S.
,
Li
,
N.
,
Schoenfeld
,
D.
,
Meng
,
H. A.
,
Lin
,
S. J.
,
Wang
,
X.
,
Wang
,
M. Y.
,
Ji
,
Z. X.
,
Zink
,
J. I.
,
Madler
,
L.
,
Castranova
,
V.
,
Lin
,
S.
, and
Nel
,
A. E.
,
2011
, “
Decreased Dissolution of ZnO by Iron Doping Yields Nanoparticles With Reduced Toxicity in the Rodent Lung and Zebrafish Embryos
,”
ACS Nano
,
5
(
2
), pp.
1223
1235
.10.1021/nn1028482
64.
Warheit
,
D. B.
,
Sayes
,
C. M.
, and
Reed
,
K. L.
,
2009
, “
Nanoscale and Fine Zinc Oxide Particles: Can In Vitro Assays Accurately Forecast Lung Hazards Following Inhalation Exposures?
,”
Environ. Sci. Technol.
,
43
(
20
), pp.
7939
7945
.10.1021/es901453p
65.
Cho
,
W. S.
,
Duffin
,
R.
,
Poland
,
C. A.
,
Howie
,
S. E. M.
,
MacNee
,
W.
,
Bradley
,
M.
,
Megson
,
I. L.
, and
Donaldson
,
K.
,
2010
, “
Metal Oxide Nanoparticles Induce Unique Inflammatory Footprints in the Lung: Important Implications for Nanoparticle Testing
,”
Environ. Health Perspect.
,
118
(
12
), pp.
1699
1706
.10.1289/ehp.1002201
66.
Ma
,
J. Y.
,
Zhao
,
H. W.
,
Mercer
,
R. R.
,
Barger
,
M.
,
Rao
,
M.
,
Meighan
,
T.
,
Schwegler-Berry
,
D.
,
Castranova
,
V.
, and
Ma
,
J. K.
,
2011
, “
Cerium Oxide Nanoparticle-Induced Pulmonary Inflammation and Alveolar Macrophage Functional Change in Rats
,”
Nanotoxicology
,
5
(
3
), pp.
312
325
.10.3109/17435390.2010.519835
67.
Peng
,
L.
,
He
,
X.
,
Zhang
,
P.
,
Zhang
,
J.
,
Li
,
Y. Y.
,
Zhang
,
J. Z.
,
Ma
,
Y. H.
,
Ding
,
Y. Y.
,
Wu
,
Z. Q.
,
Chai
,
Z. F.
, and
Zhang
,
Z. Y.
,
2014
, “
Comparative Pulmonary Toxicity of Two Ceria Nanoparticles With the Same Primary Size
,”
Int. J. Mol. Sci.
,
15
(
4
), pp.
6072
6085
.10.3390/ijms15046072
68.
Roursgaard
,
M.
,
Jensen
,
K. A.
,
Poulsen
,
S. S.
,
Jensen
,
N. E. V.
,
Poulsen
,
L. K.
,
Hammer
,
M.
,
Nielsen
,
G. D.
, and
Larsen
,
S. T.
,
2011
, “
Acute and Subchronic Airway Inflammation After Intratracheal Instillation of Quartz and Titanium Dioxide Agglomerates in Mice
,”
Thescientificworldjo
,
11
, pp.
801
825
.10.1100/tsw.2011.67
69.
Lindenschmidt
,
R. C.
,
Driscoll
,
K. E.
,
Perkins
,
M. A.
,
Higgins
,
J. M.
,
Maurer
,
J. K.
, and
Belfiore
,
K. A.
,
1990
, “
The Comparison of a Fibrogenic and 2 Nonfibrogenic Dusts by Bronchoalveolar Lavage
,”
Toxicol. Appl. Pharm.
,
102
(
2
), pp.
268
281
.10.1016/0041-008X(90)90026-Q
70.
Park
,
E. J.
,
Cho
,
W. S.
,
Jeong
,
J.
,
Yi
,
J. H.
,
Choi
,
K.
,
Kim
,
Y.
, and
Park
,
K.
,
2010
, “
Induction of Inflammatory Responses in Mice Treated With Cerium Oxide Nanoparticles by Intratracheal Instillation
,”
J. Health Sci.
,
56
(
4
), pp.
387
396
.10.1248/jhs.56.387
71.
Wingard
,
C. J.
,
Walters
,
D. M.
,
Cathey
,
B. L.
,
Hilderbrand
,
S. C.
,
Katwa
,
P.
,
Lin
,
S. J.
,
Ke
,
P. C.
,
Podila
,
R.
,
Rao
,
A.
,
Lust
,
R. M.
, and
Brown
,
J. M.
,
2011
, “
Mast Cells Contribute to Altered Vascular Reactivity and Ischemia-Reperfusion Injury Following Cerium Oxide Nanoparticle Instillation
,”
Nanotoxicology
,
5
(
4
), pp.
531
545
.10.3109/17435390.2010.530004
72.
Xue
,
L. X.
,
He
,
X.
,
Li
,
Y. Y.
,
Qu
,
M. H.
, and
Zhang
,
Z. Y.
,
2013
, “
Pulmonary Toxicity of Ceria Nanoparticles in Mice After Intratracheal Instillation
,”
J. Nanosci. Nanotechnol.
,
13
(
10
), pp.
6575
6580
.10.1166/jnn.2013.7216
73.
Ma
,
J. Y. C.
,
Young
,
S. H.
,
Mercer
,
R. R.
,
Barger
,
M.
,
Schwegler-Berry
,
D.
,
Ma
,
J. K.
, and
Castranova
,
V.
,
2014
, “
Interactive Effects of Cerium Oxide and Diesel Exhaust Nanoparticles on Inducing Pulmonary Fibrosis
,”
Toxicol. Appl. Pharmcol.
,
278
(
2
), pp.
135
147
.10.1016/j.taap.2014.04.019
74.
Minarchick
,
V. C.
,
Stapleton
,
P. A.
,
Porter
,
D. W.
,
Wolfarth
,
M. G.
,
Ciftyurek
,
E.
,
Barger
,
M.
,
Sabolsky
,
E. M.
, and
Nurkiewicz
,
T. R.
,
2013
, “
Pulmonary Cerium Dioxide Nanoparticle Exposure Differentially Impairs Coronary and Mesenteric Arteriolar Reactivity
,”
Cardiovasc. Toxicol.
,
13
(
4
), pp.
323
337
.10.1007/s12012-013-9213-3
75.
Dick
,
C. A. J.
,
Brown
,
D. M.
,
Donaldson
,
K.
, and
Stone
,
V.
,
2003
, “
The Role of Free Radicals in the Toxic and Inflammatory Effects of Four Different Ultrafine Particle Types
,”
Inhalation Toxicol.
,
15
(
1
), pp.
39
52
.10.1080/08958370304454
76.
Gelli
,
K.
,
Porika
,
M.
, and
Anreddy
,
R. N. R.
,
2015
, “
Assessment of Pulmonary Toxicity of MgO Nanoparticles in Rats
,”
Environ. Toxicol.
,
30
(
3
), pp.
308
314
.10.1002/tox.21908
77.
Zhang
,
Q. W.
,
Kusaka
,
Y.
,
Sato
,
K.
,
Nakakuki
,
K.
,
Kohyama
,
N.
, and
Donaldson
,
K.
,
1998
, “
Differences in the Extent of Inflammation Caused by Intratracheal Exposure to Three Ultrafine Metals: Role of Free Radicals
,”
J. Toxicol. Environ. Health A
,
53
(
6
), pp.
423
438
.10.1080/009841098159169
78.
Horie
,
M.
,
Fukui
,
H.
,
Endoh
,
S.
,
Maru
,
J.
,
Miyauchi
,
A.
,
Shichiri
,
M.
,
Fujita
,
K.
,
Niki
,
E.
,
Hagihara
,
Y.
,
Yoshida
,
Y.
,
Morimoto
,
Y.
, and
Iwahashi
,
H.
,
2012
, “
Comparison of Acute Oxidative Stress on Rat Lung Induced by Nano and Fine-Scale, Soluble and Insoluble Metal Oxide Particles: NiO and TiO2
,”
Inhalation Toxicol.
,
24
(
7
), pp.
391
400
.10.3109/08958378.2012.682321
79.
Kadoya
,
C.
,
Ogami
,
A.
,
Morimoto
,
Y.
,
Myojo
,
T.
,
Oyabu
,
T.
,
Nishi
,
K.
,
Yamamoto
,
M.
,
Todoroki
,
M.
, and
Tanaka
,
I.
,
2012
, “
Analysis of Bronchoalveolar Lavage Fluid Adhering to Lung Surfactant-Experiment on Intratracheal Instillation of Nickel Oxide With Different Diameters
,”
Ind. Health
,
50
(
1
), pp.
31
36
.10.2486/indhealth.MS1253
80.
Ogami
,
A.
,
Morimoto
,
Y.
,
Myojo
,
T.
,
Oyabu
,
T.
,
Murakami
,
M.
,
Todoroki
,
M.
,
Nishi
,
K.
,
Kadoya
,
C.
,
Yamamoto
,
M.
, and
Tanaka
,
I.
,
2009
, “
Pathological Features of Different Sizes of Nickel Oxide Following Intratracheal Instillation in Rats
,”
Inhalation Toxicol.
,
21
(
10
), pp.
812
818
.10.1080/08958370802499022
81.
Cho
,
W. S.
,
Duffin
,
R.
,
Poland
,
C. A.
,
Duschl
,
A.
,
Oostingh
,
G. J.
,
MacNee
,
W.
,
Bradley
,
M.
,
Megson
,
I. L.
, and
Donaldson
,
K.
,
2012
, “
Differential Pro-Inflammatory Effects of Metal Oxide Nanoparticles and Their Soluble Ions In Vitro and In Vivo; Zinc and Copper Nanoparticles, but Not Their Ions, Recruit Eosinophils to the Lungs
,”
Nanotoxicology
,
6
(
1
), pp.
22
35
.10.3109/17435390.2011.552810
82.
Cho
,
W. S.
,
Duffin
,
R.
,
Howie
,
S. E. M.
,
Scotton
,
C. J.
,
Wallace
,
W. A. H.
,
MacNee
,
W.
,
Bradley
,
M.
,
Megson
,
I. L.
, and
Donaldson
,
K.
,
2011
, “
Progressive Severe Lung Injury by Zinc Oxide Nanoparticles; the Role of Zn2+ Dissolution Inside Lysosomes
,”
Part. Fibre Toxicol.
,
8
(
1
), p. 27.10.1186/1743-8977-8-27
83.
Nishi
,
K.
,
Morimoto
,
Y.
,
Ogami
,
A.
,
Murakami
,
M.
,
Myojo
,
T.
,
Oyabu
,
T.
,
Kadoya
,
C.
,
Yamamoto
,
M.
,
Todoroki
,
M.
,
Hirohashi
,
M.
,
Yamasaki
,
S.
,
Fujita
,
K.
,
Endo
,
S.
,
Uchida
,
K.
,
Yamamoto
,
K.
,
Nakanishi
,
J.
, and
Tanaka
,
I.
,
2009
, “
Expression of Cytokine-Induced Neutrophil Chemoattractant in Rat Lungs by Intratracheal Instillation of Nickel Oxide Nanoparticles
,”
Inhalation Toxicol.
,
21
(
12
), pp.
1030
1039
.10.1080/08958370802716722
84.
Slob
,
W.
,
2002
, “
Dose-Response Modeling of Continuous Endpoints
,”
Toxicol. Sci.
, 66(
2
), pp.
298
312
.10.1093/toxsci/66.2.298
85.
Ramchandran
,
V.
, and
Gernand
,
J. M.
,
2020
, “
Examining the In Vivo Pulmonary Toxicity of Engineered Metal Oxide Nanomaterials Using a Genetic Algorithm-Based Dose-Response-Recovery Clustering Model
,”
Comput. Toxicol.
,
13
, p.
100113
.10.1016/j.comtox.2019.100113
86.
Pauluhn
,
J.
,
2010
, “
Multi-Walled Carbon Nanotubes (Baytubes (R)): Approach for Derivation of Occupational Exposure Limit
,”
Regul. Toxicol. Pharmcol.
,
57
(
1
), pp.
78
89
.10.1016/j.yrtph.2009.12.012
87.
Oberdorster
,
G.
,
1995
, “
Lung Particle Overload - Implications for Occupational Exposures to Particles
,”
Regul. Toxicol. Pharmcol.
,
21
(
1
), pp.
123
135
.10.1006/rtph.1995.1017
88.
The Mathworks
,
2017
,
MATLAB (2017b)
,
The Mathworks
, Natick, MA.
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