Archives of Toxicology

, Volume 88, Issue 8, pp 1619–1629 | Cite as

Lung tumors in mice induced by “whole-life” inorganic arsenic exposure at human-relevant doses

  • Michael P. Waalkes
  • Wei Qu
  • Erik J. Tokar
  • Grace E. Kissling
  • Darlene Dixon
Genotoxicity and Carcinogenicity


In mice, inorganic arsenic in the drinking water in the parts per million range via the dam during in utero life or with whole-life exposure is a multi-site carcinogen in the offspring. However, human arsenic exposure is typically in the parts per billion (ppb) range. Thus, we studied “whole-life” inorganic arsenic carcinogenesis in mice at levels more relevant to humans. Breeder male and female CD1 mice were exposed to 0, 50, 500 or 5,000 ppb arsenic (as sodium arsenite) in the drinking water for 3 weeks prior to breeding, during pregnancy and lactation, and after weaning (at week 3) groups of male and female offspring (initial n = 40) were exposed for up to 2 years. Tumors were assessed in these offspring. Arsenic exposure had no effect on pregnant dam weights or water consumption, litter size, offspring birthweight or weight at weaning compared to control. In male offspring mice, arsenic exposure increased (p < 0.05) bronchiolo-alveolar tumor (adenoma or carcinoma) incidence at 50-ppb group (51 %) and 500-ppb group (54 %), but not at 5,000-ppb group (28 %) compared to control (22 %). These arsenic-induced bronchiolo-alveolar tumors included increased (p < 0.05) carcinoma at 50-ppb group (27 %) compared to controls (8 %). An increase (p < 0.05) in lung adenoma (25 %) in the 50-ppb group compared to control (11 %) occurred in female offspring. Thus, in CD1 mice whole-life arsenic exposure induced lung tumors at human-relevant doses (i.e., 50 and 500 ppb).


Arsenic Carcinogenesis Mice Whole-life exposure Lung cancer 



The authors wish to thank Dr. Bhalchandra Diwan, NCI-Frederick for aid with experimental design, Drs. Thayer, Sills and Bucher, DNTP, for critical evaluation of this manuscript, Dan Logsdon and Mark Schrader NCI-Frederick for expert technical assistance in animal husbandry, for provision of critical information on diet and water, and provision of diet samples, and Matthew Bell, DNTP, for assistance with graphics. This research was supported in part by the DNTP, NIEHS and in part by the National Cancer Institute, Center for Cancer Research.

Supplementary material

204_2014_1305_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 19 kb)
204_2014_1305_MOESM2_ESM.docx (19 kb)
Supplementary material 2 (DOCX 19 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2014

Authors and Affiliations

  • Michael P. Waalkes
    • 1
  • Wei Qu
    • 1
  • Erik J. Tokar
    • 1
  • Grace E. Kissling
    • 2
  • Darlene Dixon
    • 3
  1. 1.Inorganic Toxicology Group, National Toxicology Program Laboratory, Division of the National Toxicology ProgramNational Institute of Environmental Health SciencesResearch Triangle ParkUSA
  2. 2.Biostatistics Branch, Division of Intramural ResearchNational Institute of Environmental Health SciencesResearch Triangle ParkUSA
  3. 3.Molecular Pathogenesis Group, National Toxicology Program Laboratory, DNTPNational Institute of Environmental Health SciencesResearch Triangle ParkUSA

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