Physiologically-Based Pharmacokinetic/Clonal Growth Modeling: Predicting Cancer Potential of Chemical Mixture

Details

• Personal Author:
  Yang RSH
• Description:
  Worker exposure to chemicals is rarely, if ever, confined to a single chemical. Other than the possible occupationally related chemical exposures, the intake of foods, drinks including alcoholic beverages, medicines, the use of cosmetics and toiletries, and the exposure to environmental contaminants reflect the complexity and breadth of the issues related to multiple-chemical exposure. In order to protect our workers' health from chemical insults, among other things, a very important and relevant question to ask is: Given the complexity of almost limitless number of potential chemical mixtures, do we have any means to predict the toxicity of a given chemical mixture at different dose levels? Our laboratory at Colorado State University has been working on the answer to this particular question for the past 16 years. Our approach has been based on the beliefs that: (1) the potential combinations of chemicals in the environment approaches infinity; since we cannot work on "infinity," we must concentrate our effort on a finite system, the human body; (2) the only efficient and realistic way to handle the complexity of astronomically large number of chemical mixtures in the environment is to integrate biologically-based computer modeling with very focused laboratory experimental work; and (3) we must develop a predictive tool for the toxicology of chemical mixtures utilizing fully the recent advance in computer technology and biology. In this project, we devote our effort on physiologically-based pharmacokinetic (PBPK) modeling and clonal growth modeling. The former is "Pharmacokinetics" which is, in essence, "What the body does to the chemical(s)?" and the latter is "Pharmacodynamics" which is, in essence, "What the chemical(s) does to the body?" Pharmacokinetics and pharmacodynamics form an overlapping continuum of the toxicological processes of the chemical(s) in our body. The three model chemicals used in this project are hexachlorobenzene (HCB), 3, 3',4,4', 5-pentachlorobiphenyl (PCBI26), and arsenic. We consider them as "model chemicals" because what is important is the development of the approach, a predictive tool; the identities of the chemicals are not important. The laboratory experimental system we used for assessing carcinogenic potentials of the chemicals is a time-course medium-term liver foci bioassay using the expression of placental form of glutathione-S-transferase (GST-P) in the liver cell as a biomarker for initiated cells. We used the experimentally generated data to calibrate the computer models and we believe that we have developed a preliminary tool for the prediction of carcinogenic potential of chemical(s) based on: (1) increasing rate and size of GST-P positive foci in expanded 6- month time-course liver foci bioassays; (2) the differential rates of GST-P positive cell birth and cell death in clonal growth modeling; and (3) mechanistic considerations involving the over expression of transforming growth factor-alpha (TGF-a) and the under expression of TGF-BII receptor in the GST-P positive foci. Since our group takes a team approach toward research endeavors, all projects are interwoven and they were aiming at the same goal of developing a predictive tool for chemical mixture toxicity. Therefore, closely related development includes our recent effort on biochemical reaction network modeling, which is computer modeling of enzymatic reaction networks of chemical mixtures at the molecular biotransformation level. This technology, reaction network modeling, has been used successfully in the computer simulation of petroleum oil refinery. It can easily handle thousands of chemicals and tens of thousands reactions involved in the oil refinery processes. We are the first group transplanted this technology for biomedical applications. We are still at the beginning stage of this development; some progress and examples are provided in the publication list. This report was delayed for a year because of two main reasons: (1) We expanded our animal experiments from 8-week studies to multiple 6- to 9-months studies due to the necessity of examining more advanced cellular transformations in the GST-P positive liver foci. We needed the extra time to collect the data for preparing a more meaningful final report; and (2) Due to administrative decision at the University level beyond our control, we had to move out of a building on the Foothills Campus where our laboratories reside to a new set of laboratories on the main campus of Colorado State University. This happened in June 2005 and it took us a long time to get things in operational mode. The preparation of this Abstract has followed the CDC instruction to provide a summary of our thinking, progress, and result for the benefit of a general audience. Much more technical details are provided in the sections below. [Description provided by NIOSH]
• Subjects:
  Arsenic Benzene Biochemistry Biological Assay Biphenyl Compounds Carcinogens Hazardous Substances Inorganic Chemicals Occupational Health Radiation Dosimeters Safety

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• Keywords:
  Benzenes Bioassays Biochemical Analysis Biphenyls Cellular Reactions Chemical Hazards Chemical Safety Dosimetry Humans Liver Cells Mixed Exposures Molecular Biology Pharmacodynamics Toxic Materials

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• Series:
  Grant Final Reports
• Publisher:
  National Institute for Occupational Safety and Health
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Final Grant Report
• Place as Subject:
  Colorado ; OSHA Region 8
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  OEP - Office of Extramural Programs
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  1-40
• NIOSHTIC Number:
  nn:20052173
• Citation:
  Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R01-OH-007556, 2006 Jun; :1-40
• Contact Point Address:
  Raymond S. H. Yang, Ph.D., Professor of Toxicology, Department of Environmental and Radiological Health Sciences, Colorado State University, 137A Physiology Building, 1680 Campus Delivery, Fort Collins, CO 80523-1680
• Email:
  raymond.yang@colostate.edu
• CAS Registry Number:
  Arsenic (CAS RN 7440-38-2) ; Hexachlorobenzene (CAS RN 118-74-1) ; PCB 126 (CAS RN 57465-28-8)
• Federal Fiscal Year:
  2006
• NORA Priority Area:
  Research Tools and Approaches: Risk Assessment Methods
• Performing Organization:
  Colorado State University - Fort Collins
• Peer Reviewed:
  False
• Start Date:
  20010601
• Source Full Name:
  National Institute for Occupational Safety and Health
• End Date:
  20040531
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:3e72855dd93fd8c5075a71b804953201460380a94e1e25c74c73157781e07f6c62838986b59a394706937fe3dd2d928c82b5df9adcf82f3738aa1951bf31f725
• Download URL:
  https://stacks.cdc.gov/view/cdc/218692/cdc_218692_DS1.pdf
• File Type:
  [PDF - 16.05 MB ]