Annual Meeting Program - Society of Toxicology

Society of Toxicology 2008
Program Description (Continued)
Abstract #
Reduction of protein-bound metal/metalloid ions [Ni or Cr(VI)ions] inside
cells leads to oxygen radical generation, and 8-OH-dG, which leads to mutagenesis
and gene amplification. Low doses of Pb, Cd, and As also interact
to induce oxidative protein damage and 8-hydroxy-dG damage in DNA.
Studies of metal ions in yeast cells indicate that many metal ions cause
substantial global de-regulation of gene expression in yeast. In mammalian
cells, Ni(II)ions cause chromosome aberrations and amplification of
onocogenes, leading to over-expression of proto-oncogene mRNAs and
proteins and expression of mutated oncogene protein products. Ni(II)ions
also cause chromatin condensation and inhibition of histone demethylases.
This then leads to DNA methylation and silencing of many genes, including
tumor suppressor genes. The combinationn of activation of oncogenes and
inactivation of tumor suppressor genes by metal ions, leads to loss of transcription
of genes controlled by actively transcribed tumor suppressor genes
and aberrantly high expression of genes controlled by proto-oncogenes,
in mammalian cells. This results in global disruption of gene expression
in cells. Approximately 150 genes are aberrantly expressed in Ni(II)transformed
cell lines. The resultant global disruption in cellular gene expression
leads to neoplastic transformation of cells, hence carcinogenesis.
#1284 1:30 MOLECULAR MECHANISMS AND
MOLECULAR BIOLOGY OF METAL
CARCINOGENESIS: CHEMISTRY,
MOLECULAR GENETICS, EPIGENETICS,
AND ABERRATIONS IN GENE
EXPRESSION. J. R. Landolph 1,2,3 . 1 Department
of Molecular Microbiology and Immunology,
University of Southern California, Los Angeles,
CA, 2 Department of Pathology, University of
Southern California, Los Angeles, CA and 3 USC/
Norris Comprehensive Cancer Center, University of
Southern California, Los Angeles, CA.
#1285 1:35 MOLECULAR TOXICOLOGY OF
TRANSITION METALS: FROM YEAST TO
MAN. J. H. Freedman. LMT, NIEHS, NIH, DHHS,
Research Triangle Park, NC.
#1286 2:05 CHEMISTRY AND BIOLOGY OF
CHROMIUM CARCINOGENESIS. A.
Zhitkovich. Brown University, Providence, RI.
#1287 2:35 INSOLUBLE NICKEL COMPOUNDS
INDUCE GENOTOXIC AND EPIGENETIC
EVENTS, GLOBAL DISRUPTION OF GENE
EXPRESSION, AND MORHOLOGICAL/
NEOPLASTIC TRANSFORMATION OF
10T1/2 MOUSE EMBRYO CELLS. J. R.
Landolph 1,2,3 , A. DeSilva 2,3 , H. K. Lee 1,2 , N.
Garg 1,2 and D. Fleck 1,2 . 1 Department of Molecular
Microbiology and Immunology, University of
Southern California, Los Angeles, CA, 2 Department
of Pathology, University of Southern California,
Los Angeles, CA and 3 USC/Norris Comprehensive
Cancer Center, University of Southern California,
Los Angeles, CA.
#1288 3:05 EPIGENETIC MECHANISMS OF NICKEL
ION CARCINOGENESIS BY INHIBITION
OF HISTONE DEMETHYLASES ( H3K9).
M. Costa 1,2 and H. Chen 1 . 1 Env Med, New York
University School of Medicine, New York and
2
Pharmacology, New York University Cancer
Institute, New York University Schoolx of Medicine,
New York.
#1289 3:35 INTERACTIONS AMONG ARSENIC,
CADMIUM, AND LEAD IN CAUSING
TOXICITY AND CARCINOGENESIS. B. A.
Fowler 1 , G. Wang 2 and M. H. Whittaker 3 . 1 Agency
for Toxic Substances and Disease Registry, Atlanata,
GA, 2 M. D. Anderson Cancer Center, Houston, TX
and 3 ToxServices LLC, Washington, DC.
4:05 QUESTIONS FROM THE AUDIENCE.
Abstract #
Tuesday Afternoon, March 18
1:30 PM to 4:15 PM
Room 6A
Developmental Basis of Disease
WORKSHOP SESSION: STRATEGIES FOR ASSESSING
DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY OF
BIO-PHARMACEUTICALS
Chairperson(s): Mark Hurtt, Pfizer, Inc., Groton, CT and Barbara Davis,
Millennium Pharmaceutical, Inc., Cambridge, MA.
Endorsed by:
Reproductive and Developmental Toxicology Specialty Section*
The current ICH Guidance (S6 Preclinical Safety Evaluation of Biotechnology-Derived
Pharmaceuticals, July 1997) for reproductive performance
and developmental toxicity studies describes a case-by-case situation for
every new entity. “The need for reproductive/developmental toxicity studies
is dependent upon the product, clinical indication and intended patient
population. The specific study design and dosing schedule may be modified
based on issues related to species specificity, immunogenicity, biological
activity, and/or a long elimination half-life.” In addition to the lack of
specific guidance, development of monoclonal antibodies and other biological
modalities for therapy presents some challenges to traditional practices
for assessing developmental and reproductive toxicity. The characteristics of
target specificity without off-target toxicity attributed to this type of therapy
brings into question the rationale and approaches for standard testing protocols,
including the choice of nonclinical test species. Of particular concern
is the increased emphasis on using non-human primates as a primary test
species in reproductive studies. Working groups are addressing the scientific
and ethical concerns of using non-human primates and developing
strategies for standard toxicology testing (Chapman K, Pullen N, Graham
M, Ragan I. Preclinical safety testing of monoclonal antibodies: the significance
of species relevance. Nat Rev Drug Discov. 2007:120-6). A focused
discussion of the strategies for testing bio-pharmaceuticals for potential
reproductive and developmental toxicity is merited. This workshop will
bring together experts in the fields of reproductive and developmental toxicology,
biologics, and regulatory agencies to discuss relevant reproductive
testing strategies for bio-pharmaceuticals.
#1290 1:30 STRATEGIES FOR ASSESSING
DEVELOPMENTAL AND
REPRODUCTIVE TOXICOLOGY OF BIO-
PHARMACEUTICALS. M. Hurtt 1 and B. Davis 2 .
1
Drug Safety, Pfizer, Groton, CT and 2 Millennium
Pharmaceutical Inc, Cambridge, MA.
#1291 1:45 ISSUES IN DEVELOPMENTAL
AND REPRODUCTIVE TESTING
OF BIOPHARMACEUTICALS AND
COMMUNICATION OF HUMAN RISK. J.
Cavagnaro. Access BIO, Boyce, VA.
#1292 2:15 FDA REGULATORY PERSPECTIVE ON
REPRODUCTIVE AND DEVELOPMENTAL
TESTING FOR BIOPHARMACEUTICALS. H.
Ghantous. CDER/DAVP, U.S. -FDA, Silver Spring,
MD.
#1293 2:45 EU REGULATORY PERSPECTIVE ON
TOXICITY TESTING FOR REPRODUCTIVE
AND DEVELOPMENTAL TOXICITY. J. W.
van der Laan. Centre for Biological Medicines and
Medical Technology, RIVM, Bilthoven, Netherlands.
Sponsor: M. Hurtt.
#1294 3:15 APPROACHES TO TESTING FOR
REPRODUCTIVE AND DEVELOPMENTAL
TOXICITY: USE OF NONHUMAN
PRIMATES. G. J. Chellman. Preclinical Services,
Charles River Laboratories, Sparks, NV.
Tuesday
up-to-date information at www.toxicology.org 199