Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes

Linda M. Sargent, Dale W. Porter, Lauren M. Staska, Ann F. Hubbs, David T. Lowry, Lori Battelli, Katelyn J. Siegrist, Michael L. Kashon, Robert R. Mercer, Alison K. Bauer, Bean T. Chen, Jeffrey L Salisbury, David Frazer, Walter McKinney, Michael Andrew, Shuji Tsuruoka, Morinobu Endo, Kara L. Fluharty, Vince Castranova, Steven H. Reynolds

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Background: Engineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m3, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation. Results: Twenty-three percent of the filtered air controls, 26.5% of the MWCNT-exposed, and 51.9% of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5% of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17months after exposure. Indeed, 62% of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13% of the mice that received filtered air, 22% of the MCA-exposed, or 14% of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5%). Five mice (9%) exposed to MCA and MWCNT and 1 (1.6%) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms. Conclusions: These data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT.

Original languageEnglish (US)
Article number3
JournalParticle and Fibre Toxicology
Volume11
Issue number1
DOIs
StatePublished - Jan 9 2014

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Inhalation Exposure
Carbon Nanotubes
Bronchiolo-Alveolar Adenocarcinoma
Tumors
Air
Lung
Adenocarcinoma of lung
Neoplasms
Adenoma
Sun hoods
Health hazards
Lubricants
Sunscreening Agents
Methylcholanthrene
Corn Oil
Cosmetics
Paint
Euthanasia
Single-walled carbon nanotubes (SWCN)
Mesothelioma

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Toxicology

Cite this

Sargent, L. M., Porter, D. W., Staska, L. M., Hubbs, A. F., Lowry, D. T., Battelli, L., ... Reynolds, S. H. (2014). Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes. Particle and Fibre Toxicology, 11(1), [3]. https://doi.org/10.1186/1743-8977-11-3

Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes. / Sargent, Linda M.; Porter, Dale W.; Staska, Lauren M.; Hubbs, Ann F.; Lowry, David T.; Battelli, Lori; Siegrist, Katelyn J.; Kashon, Michael L.; Mercer, Robert R.; Bauer, Alison K.; Chen, Bean T.; Salisbury, Jeffrey L; Frazer, David; McKinney, Walter; Andrew, Michael; Tsuruoka, Shuji; Endo, Morinobu; Fluharty, Kara L.; Castranova, Vince; Reynolds, Steven H.

In: Particle and Fibre Toxicology, Vol. 11, No. 1, 3, 09.01.2014.

Research output: Contribution to journalArticle

Sargent, LM, Porter, DW, Staska, LM, Hubbs, AF, Lowry, DT, Battelli, L, Siegrist, KJ, Kashon, ML, Mercer, RR, Bauer, AK, Chen, BT, Salisbury, JL, Frazer, D, McKinney, W, Andrew, M, Tsuruoka, S, Endo, M, Fluharty, KL, Castranova, V & Reynolds, SH 2014, 'Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes', Particle and Fibre Toxicology, vol. 11, no. 1, 3. https://doi.org/10.1186/1743-8977-11-3
Sargent, Linda M. ; Porter, Dale W. ; Staska, Lauren M. ; Hubbs, Ann F. ; Lowry, David T. ; Battelli, Lori ; Siegrist, Katelyn J. ; Kashon, Michael L. ; Mercer, Robert R. ; Bauer, Alison K. ; Chen, Bean T. ; Salisbury, Jeffrey L ; Frazer, David ; McKinney, Walter ; Andrew, Michael ; Tsuruoka, Shuji ; Endo, Morinobu ; Fluharty, Kara L. ; Castranova, Vince ; Reynolds, Steven H. / Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes. In: Particle and Fibre Toxicology. 2014 ; Vol. 11, No. 1.
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title = "Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes",
abstract = "Background: Engineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m3, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation. Results: Twenty-three percent of the filtered air controls, 26.5{\%} of the MWCNT-exposed, and 51.9{\%} of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5{\%} of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17months after exposure. Indeed, 62{\%} of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13{\%} of the mice that received filtered air, 22{\%} of the MCA-exposed, or 14{\%} of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5{\%}). Five mice (9{\%}) exposed to MCA and MWCNT and 1 (1.6{\%}) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms. Conclusions: These data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT.",
author = "Sargent, {Linda M.} and Porter, {Dale W.} and Staska, {Lauren M.} and Hubbs, {Ann F.} and Lowry, {David T.} and Lori Battelli and Siegrist, {Katelyn J.} and Kashon, {Michael L.} and Mercer, {Robert R.} and Bauer, {Alison K.} and Chen, {Bean T.} and Salisbury, {Jeffrey L} and David Frazer and Walter McKinney and Michael Andrew and Shuji Tsuruoka and Morinobu Endo and Fluharty, {Kara L.} and Vince Castranova and Reynolds, {Steven H.}",
year = "2014",
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T1 - Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes

AU - Sargent, Linda M.

AU - Porter, Dale W.

AU - Staska, Lauren M.

AU - Hubbs, Ann F.

AU - Lowry, David T.

AU - Battelli, Lori

AU - Siegrist, Katelyn J.

AU - Kashon, Michael L.

AU - Mercer, Robert R.

AU - Bauer, Alison K.

AU - Chen, Bean T.

AU - Salisbury, Jeffrey L

AU - Frazer, David

AU - McKinney, Walter

AU - Andrew, Michael

AU - Tsuruoka, Shuji

AU - Endo, Morinobu

AU - Fluharty, Kara L.

AU - Castranova, Vince

AU - Reynolds, Steven H.

PY - 2014/1/9

Y1 - 2014/1/9

N2 - Background: Engineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m3, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation. Results: Twenty-three percent of the filtered air controls, 26.5% of the MWCNT-exposed, and 51.9% of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5% of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17months after exposure. Indeed, 62% of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13% of the mice that received filtered air, 22% of the MCA-exposed, or 14% of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5%). Five mice (9%) exposed to MCA and MWCNT and 1 (1.6%) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms. Conclusions: These data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT.

AB - Background: Engineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m3, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation. Results: Twenty-three percent of the filtered air controls, 26.5% of the MWCNT-exposed, and 51.9% of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5% of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17months after exposure. Indeed, 62% of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13% of the mice that received filtered air, 22% of the MCA-exposed, or 14% of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5%). Five mice (9%) exposed to MCA and MWCNT and 1 (1.6%) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms. Conclusions: These data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT.

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