title: Application of transcriptional benchmark dose values in quantitative cancer and noncancer risk assessment.
abstract: The traditional approach for estimating noncancer and cancer reference values in quantitative chemical risk assessment is time and resource intensive. The extent and nature of the studies required under the traditional approach has limited the number of chemicals with published risk assessments. In this study, female mice were exposed for 13 weeks to multiple concentrations of five chemicals that were positive in a 2-year cancer bioassay. Traditional histological and organ weight changes were evaluated, and gene expression microarray analysis was performed on the target tissues. The histological, organ weight changes, and the original tumor incidences in the original cancer bioassay were analyzed using standard benchmark dose (BMD) methods to identify noncancer and cancer points of departure, respectively. The dose-related changes in gene expression were also analyzed using a BMD approach and the responses grouped based on cellular biological processes. A comparison of the transcriptional BMD values with those for the traditional noncancer and cancer apical endpoints showed a high degree of correlation for specific cellular biological processes. For chemicals with human exposure data, the transcriptional BMD values were also used to calculate a margin of exposure. The margins of exposure ranged from 1900 to 54,000. Both the correlation between the BMD values for the transcriptional and apical endpoints and the margin of exposure analysis suggest that transcriptional BMD values may be used as potential points of departure for noncancer and cancer risk assessment.
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA. rthomas@thehamner.org
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Allen
authors.forename: Scott C
authors.initials: SC
authors.lastname: Wesselkamper
authors.forename: Nina Ching Y
authors.initials: NC
authors.lastname: Wang
authors.forename: Jason C
authors.initials: JC
authors.lastname: Lambert
authors.forename: Janet K
authors.initials: JK
authors.lastname: Hess-Wilson
authors.forename: Q Jay
authors.initials: QJ
authors.lastname: Zhao
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests / Q000379:methods; D002274:Carcinogens, Environmental / Q000633:toxicity*; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D004781:Environmental Exposure / Q000009:adverse effects / Q000032:analysis; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D012016:Reference Values; D018570:Risk Assessment; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D002274:Carcinogens, Environmental