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Environmental Carcinogenesis Division (ECD)
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Research in this division focuses on improved understanding of environmentally induced mutagenesis and carcinogenesis, with special emphasis on the underlying mechanisms, for incorporation into human cancer risk assessment models. The program uses cellular, animal and computer models for assessing responses to a broad range of environmental chemicals and chemical mixtures. The current emphasis is air toxics (especially particulate matter), water disinfection byproducts, arsenic, chemicals on the EPA's chemical contaminant list, and human health risk assessment strategies. The overall aim is to provide data for use in human cancer risk assessment models. Examples of the approaches are to identify hazard, to assess dose and tumor response through the use of informative biomarkers, and to develop dose response curves for tumor outcome in humans using rodent tumor data and/or cellular indicators of tumorigenicity, such as specific genetic alterations, regenerative cell proliferation following cytotoxicity, or preneoplastic lesions. A significant component of the research effort is directed towards better understanding the mechanisms underlying tumor development for specific tumor types following particular exposure scenarios. Thus, the division has the capability to influence the development of the cancer risk assessment process.
The objective of the mutagenesis research is to understand the chemical induction of somatic and germ cell mutations as a basis for improving risk assessments for cancer and heritable mutations, respectively. The program involves molecular and cellular genetics, that includes studies of mutagenesis and cytogenetics in vitro and in vivo. Among the responses studied in somatic and germinal cells are gene point mutations, chromosomal alterations, primary damage to DNA, the repair of DNA damage, and other effects on cellular processes such as transcription, DNA replication and cell cycle control, all of which can be involved in tumor formation.
The carcinogenesis component of the research program is aimed at achieving a better understanding of chemical carcinogenesis in order to improve cancer risk assessments. Research is undertaken to examine the ability of chemicals to influence the induction, promotion, and progression of tumors, while computer models are utilized to relate the molecular structure of chemicals to potential biological effects. Studies at the molecular, cellular, and whole organism levels are conducted to develop dosimetry and mechanism of action models that will enhance the ability to extrapolate from rodents to humans.
Efforts are also aimed at identifying and validating biological markers for genotoxicants at the molecular and cellular levels that can provide quantitative data on exposure and dose, and that can produce meaningful information about the relationships among early biochemical changes, preneoplastic lesions, and cancerous lesions. This research will advance the field of molecular epidemiology and will aid in the development of biologically based dose-response models for mutagenicity and carcinogenicity. Along similar lines research on pollutant mixtures is designed to develop, validate, and refine bioanalytical methods to assess and characterize human exposure, molecular dose, and associated cellular effects.
The research of the division makes use of the most current techniques in molecular and cellular toxicology, including the use of DNA/RNA arrays, automated DNA sequencing, mass spectrometry, and in situ hybridization. The broad range of expertise provides for a multi-disciplinary approach for addressing the responses of organisms to environmental chemicals and for the use of the data developed in the cancer risk assessment process.
