Toxicology and Applied Pharmacology 233 (2008) 5–6

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Toxicology and Applied Pharmacology

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Announcement

Biomarkers of Exposure and Effects: Presentations at the 2007Toxicology and Risk Assessment Conference

Identification of new biomarkers is rapidly increasing with theavailability of advanced and sensitive techniques. With the continuingadvances in genomics, proteomics and other computational technol-ogies, an improvement in designing future biomarkers studies isexpected, which will facilitate the identification of risk to humanpopulation. For example, ProteinChip technology coupled withsurface-enhanced laser desorption/ionization time-of-flight massspectrometry facilitates protein profiling of complex biologicalmixtures. These biomarkers of exposure, effect and susceptibility areeffectively being used in providing new insights into the progressionof a disease.

A session entitled “Biomarkers of Exposure and Effects”was held inApril 2007 in Cincinnati, OH at the 2007 Toxicology and RiskAssessment Conference. The purpose of this session was to explorebiomarkers using new technologies and identify their use in riskassessment. This session consisted of six speakers representing bothregulatory agencies and academia. Dr. Keshava provided an overviewof the “Use of Biomarkers in Risk Assessment”. She briefly discusseddifferent types of biomarkers, how they are currently used in riskassessment, what are the needs for improving identification ofbiomarkers and how they can be better used in the future in a riskassessment scenario. The next speaker, Dr. David Eastmond presented“Chromosomal Alterations as Biomarkers of Cancer and HeritableRisks in Human Populations”. He described that the emergingdiscipline of molecular epidemiology uses biomarkers of exposure,susceptibility and effect to evaluate the risk of cancer and otherdiseases in human populations. Dr. Eastmond emphasized that thisapproach had great potential for improving exposure assessment,identifying genotoxic agents as well as susceptible individuals withinthe population, detecting early pre-clinical stages of disease andexpected to allow intervention steps that could be taken to reduce theincidence of disease. His presentation focussed on how chromosomalbiomarkers of effect are being used to evaluate genetic and cancerrisks in humans. Dr. Eastmond provided examples of multi-nationalstudy that have shown an association between the incidence ofmicronuclei in peripheral blood lymphocytes and ultimate cancer risk.He mentioned that new methods such as fluorescence in situhybridization and other molecular techniques will be very useful formonitoring human populations.

In continuation of evaluating new techniques, Dr. David DeMarinipresented “Urinary Mutagenicity: A Biomarker of Genotoxic Expo-sures via Air, Water and Diet”. He emphasized that urinarymutagenicity has been shown to correlate well with other biomar-kers, including DNA and haemoglobin adducts, urinary metabolitesand chromosomal aberrations or micronuclei in peripheral bloodlymphocytes. He mentioned that urinary mutagenicity had theadvantage of providing an integrated measure of exposure to acomplex mixture of genotoxins. He described the results a series of

doi:10.1016/j.taap.2008.08.002

studies that was conducted in his laboratory. For example, they haveshown, in a case-control study of patients with colorectal polyps,which are potential precursors to colon cancer, that the un-conjugated urinary mutagenicity was predictive of risk for colorectalpolyps. Furthermore, Dr. DeMarini and his co-workers have demon-strated that urinary mutagenicity correlated with a variety of otherbiomarkers in subjects exposed to cigarette smoke, benzidine dyes,wood smoke and well-cooked pan-fired meat. Their studies alsodemonstrated that dietary interventions, such as consumption ofcruciferous vegetables, can reduce the levels of urinary mutagenicityas well as other biomarkers of exposure. Based on the results of theabove studies, Dr. DeMarini concluded that biomarkers appeared tobe more robust measures of exposure than external analyticalmeasurements of single compounds.

Dr. DeMarini's talk was followed by Dr. Sargent’s presentation on“Genetic Changes as Biomarkers of Mouse Lung Adenocarcinoma:Comparison to Human”. Dr. Sargent and her co-workers have usedmodern technologies such as spectral karyotyping (SKY), fluorescencein situ hybridization (FISH), comparative genomic hybridization(CGH), and gene expression arrays to identify biomarkers. In theirstudy, they have used early passage mouse lung adenocarcinoma cellstrains and high-invasive and low-invasive mouse lung adenocarci-noma tumor cell strain pairs to detect genetic biomarkers associatedwith mouse lung adenocarcinoma phenotype and tumor invasion.Through a series of vigorous molecular analysis, Dr. Sargent and co-authors have demonstrated increased expression of COX-2, Translin,DYRK3, NUCKS and Tubulin-α4 genes in the high-invasive cell strains.When compared to human, the authors predict that increased copynumber and expression of genes on mouse chromosome 1 may play afunctional role in lung cancer development and may aid in identifyingunique lung cancer biomarkers as well as susceptibility genes inmouse and human.

Dr. Russell spoke on “Biomarker-Based OELs and Risk Assessment”.His presentation highlighted the need for the development of a welldocumented systematic approach to validate biological endpoints. Inlight of this, Dr. Russell and his co-workers have conducted a pilotstudy to develop and demonstrate the use of a system for integratingcomplex and multifaceted data, validating biomarkers and incorpor-ating the biomarkers into an occupational exposure limit (OEL). In hispresentation Dr. Russell described that they have developed abiomarker database structure and identified decision rules to organizethe diverse types of data necessary to develop an OEL, particularly forbenzene. They have applied a suite of biomarker validationapproaches to evaluate the potential biomarkers of exposure andeffect for key chronic cancer and non-cancer endpoints; specificallythe nematotoxicity endpoints of anemia, leucopenia and leukemia.The authors have combined traditional biomarker evaluationapproaches based on the Hill criteria and regression analysis with aBayesian network approach to test and validate (or discount)biomarkers along the exposure-disease continuum. They concludedthat, although further refinement was needed for the quantitativevalidation techniques proposed, the approach and its application to

6 Announcement

OEL development and risk assessment was being employed for a caseexample of trichloroethylene.

The last speaker of the session, Dr. Weida Tong presented“Integrated Bioinformatics — An FDA Experience”. Dr. Tong empha-sized the importance of an integrated bioinformatics approach tofacilitate the data review to realize the benefits of phamacoge-nomics and toxicogenomics to the public health. In his presentation,an array of FDA efforts on phamacogenomics and toxicogenomicspowered by integrated bioinformatics was discussed. Specifically, heemphasized that FDA has issued guidance to industry on phama-cogenomics data submission that defines voluntary genomics datasubmission. To facilitate this process, an integrated FDA bioinfor-matics tool, called ArrayTrack, has been developed and is beingrefined as a review tool for managing, analyzing and interpretingthe exploratory data including genomics, proteomics and proteomicsdata in clinical and non-clinical data submission. Furthermore, acommunity-supported project — a MicroArray Quality Control(MAQC) led by FDA has been initiated to address various issuesassociated with DNA microarrys, a critical technology used in

phamacogenomics and toxicogenomics. Dr. Tong hoped that theseactivities will help best practice in bioinformatics in evaluation ofbiomarker data. The session ended with an active discussion ofquestion and answers.

Bruce FowlerAgency for Toxic Substances and Disease Registry,

Senior Biomedical Research Services, Atlanta, GA, USA

Nagalakshmi KeshavaU.S. Environmental Protection Agency, Office of Research andDevelopment, National Center for Environmental Assessment,

Washington, DC, USAE-mail address: keshava.nagu@epa.gov.

Corresponding author. National Center for EnvironmentalAssessment, Office of Research and Development,U.S. Environmental Protection Agency, B 243-01,

Research Triangle Park, NC 27711, USA.Fax: +1 919 541 0245.