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Kai H. Liao,^1,2 Daniel L. Gustafson,³ Michael H. Fox,⁴ Laura S. Chubb,¹ Kenneth F. Reardon,²
and Raymond S.H. Yang¹

Quantitative and Computational Toxicology Group, Center for Environmental Toxicology and Technology, Departments of ¹Environmental Health, ²Chemical and Bioresource Engineering, Colorado State University, Fort Collins, Colorado, USA; ³Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado, USA; ⁴Radiological Health Sciences, Colorado State University, Fort Collins, Colorado, USA

Abstract

We modified the two-stage Moolgavkar-Venzon-Knudson (MVK) model for use with Syrian hamster embryo (SHE) cell neoplastic progression. Five phenotypic stages are proposed in this model: Normal cells can either become senescent or mutate into immortal cells followed by anchorage-independent growth and tumorigenic stages. The growth of normal SHE cells was controlled by their division, death, and senescence rates, and all senescent cells were converted from normal cells. In this report, we tested the modeling of cell kinetics of the first two phenotypic stages against experimental data evaluating the effects of arsenic on SHE cells. We assessed cell division and death rates using flow cytometry and correlated cell division rates to the degree of confluence of cell cultures. The mean cell death rate was approximately equal to 1% of the average division rate. Arsenic did not induce immortalization or further mutations of SHE cells at concentrations of 2 µM and below, and chromium (3.6 µM) and lead (100 µM) had similar negative results. However, the growth of SHE cells was inhibited by 5.4 µM arsenic after a 2-day exposure, with cells becoming senescent after only 16 population doublings. In contrast, normal cells and cells exposed to lower arsenic concentrations grew normally for at least 30 population doublings. The biologically based model successfully predicted the growth of normal and arsenic-treated cells, as well as the senescence rates. Mechanisms responsible for inducing cellular senescence in SHE cells exposed to arsenic may help explain the apparent inability of arsenic to induce neoplasia in experimental animals. Key words: Arsenic, cancer modeling, cell proliferation, senescence, Syrian hamster embryo cell. Environ Health Perspect 109:1207-1213 (2001) . [Online 21 November 2001]

http://ehpnet1.niehs.nih.gov/docs/2001/109p1207-1213liao/ abstract.html

Address correspondence to R.S.H. Yang, Center for Environmental Toxicology and Technology, Colorado State University, Fort Collins, CO 80523 USA. Telephone: (970) 491-5652. Fax: (970) 491-8304. E-mail: Raymond.Yang@colostate.edu

This work was supported in part by a cooperative agreement with the Agency for Toxic Substances and Disease Registry (U61/ATU 881475) , and National Institute for Environmental Health Sciences Superfund Basic Research Program Project (P42 ES05949) and research grant (RO1ES09655) .

Received 24 October 2000 ; accepted 2 May 2001.