The Toxicologist - Society of Toxicology

eleasing 76% were read-across from Ni sulfate. No source or target substances
released 48-76% available Ni in this study. Therefore, in the absence of additional
verification data, read-across from the more conservative source substance
(i.e., Ni sulfate) was recommended. Substances read-across from Ni sulfate warrant
classification for acute (Xn;R22 and Acute Tox. 3) and reproductive (Cat 2;R61
and Repro 1B) toxicity in the EU.
299 NICKEL(II) CHLORIDE CAUSES PANCREATIC ISLET β-
CELL DEATH VIA A JNK-REGULATED
MITOCHONDRIAL APOPTOTIC PATHWAY.
D. Hung 2, 1 , K. Chen 3 , H. Wu 3 , Y. Chen 4 , C. Su 5 , C. Yen 6 , T. Lu 1 , Y. Yang 1 ,
T. Ho 7 and C. Huang 7 . 1 Graduate Institute of Drug Safety, China Medical
University, Taichung City, Taiwan, 2 Toxicology Center, China Medical University
Hospital, Taichung, Taiwan, 3 Department of Urology, China Medical University
Hospital, Taichung, Taiwan, 4 Department of Physiology, China Medical University,
Taichung, Taiwan, 5 Department of Otorhinolaryngology, Head and Neck Surgery,
Changhua Christian Hospital, Changhua, Taiwan, 6 Department of Occupational
Safety and Health, Chung Shan Medical University, Taichung, Taiwan and 7 School of
Chinese Medicine, China Medical University, Taichung, Taiwan.
Nickel is a toxic heavy metal, which is widely used in electroplating and alloys producing.
Previous studies have shown that long term exposure to nickel would lead
intoxication in several organs, such as pneumonitis, rhinitis, sinusitis, dermatitis,
nasal cavity and lung cancers. Several studies have shown that nickel possesses the
ability to induce hyperglycemia. However, the precise action and mechanism of
nickel on the growth and function of pancreatic islet β-cells are still unclear. Thus,
the present study is designed to investigate the effects and possible mechanisms of
nickel chloride (NiCl2) exposure on islet β-cell line RIN-m5F cells. The results
showed that the cell morphology of RIN-m5F cells was significantly changed 24
hours after treatment with NiCl2. The flow cytometric analysis showed that the
sub-G1 cell count and Annexin V-Cy3 fluorescence were dramatically increased in
NiCl2-treated RIN-m5F cells. Apoptosis-related caspases including caspase-3, caspase-7,
and caspase-9, were also activated in NiCl2-treated RIN-m5F cells.
Furthermore, NiCl2 could also significantly enhance the mRNA expressions of
p53, Bid, and Bak. Besides, NiCl2 increased cytochrome c release from mitochodria
to cytosol. The mitochondrial transmembrane potential was also decreased
by NiCl2. These NiCl2-induced effects could be reversed by JNK inhibitor
SP600125. Taken together, these results indicate that exposure to NiCl2 induces
the cytotoxicity and apoptosis in pancreatic islet β-cells via a JNK-regulated mitochondrial
apoptotic pathway.
300 LOW-DOSE PYRROLIDINE
DITHIOCARBAMATE/COPPER COMPLEX INDUCES
LUNG EPITHELIAL CELL APOPTOSIS VIA THE ER-
STRESS-RELATED SIGNALING PATHWAYS.
Y. Chen 1 , K. Chen 2 , C. Chen 3, 4 , H. Wu 2 , C. Su 5 , D. Hung 6, 4 , C. Yen 7 , Y.
Yang 4 and T. Lu 4 . 1 Department of Physiology, China Medical University, Taichung,
Taiwan, 2 Department of Urology, China Medical University Hospital, Taichung,
Taiwan, 3 Department of Emergency, China Medical University Hospital, Taichung,
Taiwan, 4 Graduate Institute of Drug Safety, China Medical University, Taichung,
Taiwan, 5 Department of Otorhinolaryngology, Head and Neck Surgery, Changhua
Christian Hospital, Changhua, Taiwan, 6 Toxicology Center, China Medical
University Hospital, Taichung, Taiwan and 7 Department of Occupational Safety and
Health, Chung Shan Medical University, Taichung, Taiwan.
Pyrrolidine dithiocarbamate (PDTC) is widely used in pesticides, fungicides, insecticides,
and herbicides. Copper (Cu) is a toxic heavy metal in the environment, and
an essential trace metal element in the body, which is involved in many biological
processes as a catalytic cofactor. The present study is designed to investigate the cellular
toxicity of low-dose PDTC, CuCl2, and PDTC/Cu complex exposure in lung
alveolar epithelial cells that serve primary structural and functional roles in the
lungs. The results showed that PDTC or CuCl2 alone did not affect cell viability,
but PDTC/Cu complex significantly decreased lung alveolar epithelial cell viability.
PDTC/Cu complex dramatically enhanced the phosphorylations of JNK and ERK
proteins. PDTC/Cu complex was capable of activating the apoptosis-related caspases
including caspase-9, caspase-7, and caspase-3, which could be reversed by the
addition of JNK inhibitor SP600125 or transfection of MAPK8 short hairpin
RNA. PDTC/Cu complex also induced mitochondrial dysfunction. Furthermore,
PDTC/Cu complex could trigger the expressions of ER stress-associated signaling
molecules including Grp78, Grp94, caspase-12, ATF4, and CHOP, which could be
reversed by SP600125. Taken together, these results indicate that exposure to lowdose
PDTC/Cu complex induces cytotoxicity and apoptosis in alveolar epithelial
cells via the ER-stress-related signaling pathways.
64 SOT 2011 ANNUAL MEETING
301 CHEMICAL FORM OF METALS IN TRADITIONAL
MEDICINES UNDERLINES POTENTIAL TOXICITY IN
CELL CULTURES.
Q. Wu 1 , Y. Lu 1 , J. Shi 3 , J. Liu 1, 2 and J. Shi 1 . 1 Pharmacology, Zunyi Medical
College, Zunyi, Guizhou, China, 2 Pharmacology, Toxicology & Therapeutics,
University of Kansas Medical Center, Kansas City, KS and 3 Pharmacology, Guiyang
Traditional Medical College, Guiyang, Guizhou, China.
Mercury (Hg) and arsenic (As) are frequently found in traditional medicines as sulfides,
such as cinnabar (96% as HgS) and realgar (90% as As4S4). The addition of
these mineral metals in traditional medicines has been claimed for their therapeutic
efficacy. However, Hg is highly toxic, and As is known for its carcinogenic and toxic
effects. There is a general perception that any medicinal use of such metal-containing
remedies is unacceptable. An opposing opinion is that different chemical forms
of arsenic and mercury have different toxic potentials. To clarify this question,
cinnabar, realgar, and cinnabar- and realgar-containing traditional medicine An-
Gong-Niu-Huang Wan (AGNH), were compared to well-known mercurials (HgS,
HgCl2 and MeHg) and arsenicals (As2S2, As2O3, NaAsO2, and Na2HAsO4) for
their cytotoxicity in rodent (HAPI, TRL1215) and human (HepG2, Hep3B,
FaDu) cell lines. MeHg was most toxic with LC50 of 4-20 μM, followed by
NaAsO2 (LC50, 25-250 μM) and HgCl2 (LC50, 50-100 μM), Na2HAsO4
(LC50, 60-400 μM), As2O3 (LC50, 30-900 μM), and As2S2 (LC50, 50-1000
μM). In comparison, the LC50 of realgar ranged from 250 to1500 μM; whereas
cinnabar or HgS were approximately 20,000 μM and the toxicity of AGNH was in
the range of 1500-8000 μM. Approximately 5,000-fold differences exist between
MeHg and HgS, and over 10-fold differences exist between NaAsO2 and As4S4. In
conclusion, chemical forms of metals are important factor in determine their toxicity
in traditional medicines, both cinnabar and realgar are much less toxic than
well-known mercurial and arsenicals.
302 INVESTIGATION OF TELLURIUM TOXICITY IN HT-29
AND CACO-2 HUMAN COLON CELLS.
P. Vij and D. Hardej. Department of Pharmaceutical Sciences, St. John’s University,
Queens, NY.
Tellurium (Te) is a metalloid, with no known physiologic role in humans.
Increasing use of Te compounds in industry for the production of semiconductors,
blu-ray discs, as vulcanizing agents and as catalysts for synthetic fiber production
suggests that environmental exposure will increase in the future. The neurotoxicity
of Te compounds has been documented, particularly in animal studies. Little has
been reported regarding the gastrointestinal toxicity of Te, despite the fact that ingestion
represents a major exposure route. In vitro studies confirming Te toxicity are
lacking. The purpose of this study was to investigate the toxicity of tellurium tetrachloride
(TeCl 4 ) and diphenylditelluride (DPDT) in Caco2 and Ht-29 human
colon cells. Cells from both the cell lines were grown to 90% confluency and
treated with concentrations of each compound ranging from 0.98μM to 1.0mM
for 24h. Viability was assessed by MTT and bioluminescent-based assays.
Significant decreases in viability in each cell line were seen in concentrations ranging
from 62.5μM to 1.0mM. Phase contrast and scanning electron microscopy
were performed to confirm viability results and to observe morphologic changes
consistent with toxicity. Distortion such as disruption of cell structure and blebbing
was observed in these groups. In order to investigate the mechanism of cell death,
caspase 3/7 and caspase 9 activity was assessed in the HT 29 cells using each compound.
Significant increase in caspase 3/7 and caspase 9 activity was observed in
500μM and 1.0mM concentrations indicating cell death by the intrinsic apoptotic
pathway. No significant increases in caspases were observed in HT 29 cells treated
with TeCl 4 at concentrations ranging from 125μM to 1.0mM. We conclude that
there is a significant decrease in cell viability in HT 29 and Caco2 cells treated with
both compounds in concentrations ranging from 62.5μM to 1.0mM and that HT-
29 cells treated with DPDT die via the intrinsic apoptotic pathway.
303 LUNAR DUST SIMULANT IS CYTOTOXIC BUT NOT
GENOTOXIC TO HUMAN SKIN FIBROBLAST CELLS.
R. Duffy 1, 2 ,J.Wise 1, 2 ,H. Xie 1, 2, 3 , A. Jeevaragen 4 , W. Wallace 6 , D. Hammond 4 ,
T. Shehata 5 and J. P. Wise 1, 2, 3 . 1 Wise Laboratory of Environmental and Genetic
Toxicology, University of Southern Maine, Portland, ME, 2 Maine Center for
Toxicology and Environmental Health, University of Southern Maine, Portland, ME,
3 Department of Applied Medical Science, University of Southern Maine, Portland, ME,
4 NASA Johnson Space Center, Houston, TX, 5 Maine Space Consortium, Augusta, ME
and 6 Wyle Integrated Science and Engineering, Houston, TX.
NASA is considering a permanent space station on the moon. Humans will occupy
this space station, therefore it is important to assess any health hazards present in
the lunar environment. On prior missions to the moon, the dust that composes the