Predicting Skin Permeability from Complex Chemical Mixtures: Dependency of Quantitative Structure Permeation Relationships on Biology of Skin Model Used

Details

• Personal Author:
  Brooks JD ; Riviere JE
• Description:
  Dermal absorption of topically applied chemicals usually occurs from complex chemical mixtures; yet, most attempts to quantitate dermal permeability use data collected from single chemical exposure in aqueous solutions. The focus of this research was to develop quantitative structure permeation relationships (QSPR) for predicting chemical absorption from mixtures through skin using two levels of in vitro porcine skin biological systems. A total of 16 diverse chemicals were applied in 384 treatment mixture combinations in flow-through diffusion cells and 20 chemicals in 119 treatment combinations in isolated perfused porcine skin. Penetrating chemical flux into perfusate from diffusion cells was analyzed to estimate a normalized dermal absorptive flux, operationally an apparent permeability coefficient, and total perfusate area under the curve from perfused skin studies. These data were then fit to a modified dermal QSPR model of Abraham and Martin including a sixth term to account for mixture interactions based on physical chemical properties of the mixture components. Goodness of fit was assessed using correlation coefficients (r2), internal and external validation metrics (q 2 LOO qLOO2 , q 2 L25% qL25%2 , q 2 EXT qEXT2 ), and applicable chemical domain determinations. The best QSPR equations selected for each experimental biological system had r2 values of 0.69-0.73, improving fits over the base equation without the mixture effects. Different mixture factors were needed for each model system. Significantly, the model of Abraham and Martin could also be reduced to four terms in each system; however, different terms could be deleted for each of the two biological systems. These findings suggest that a QSPR model for estimating percutaneous absorption as a function of chemical mixture composition is possible and that the nature of the QSPR model selected is dependent upon the biological level of the in vitro test system used, both findings having significant implications when dermal absorption data are used for in vivo risk assessments. [Description provided by NIOSH]
• Subjects:
  Animals Hazardous Substances Insecticides Occupational Health Safety Skin Toxicology
• Keywords:
  Animal Studies Author Keywords: Chemical Mixtures Chemical Hazards Dermal Absorption Dermal Exposures Dose Response In Vitro Models In Vitro Study Models Percutaneous/Dermal Absorption Pesticide Risk Assessment Pesticides And Agricultural Chemicals Physiological Effects QSAR QSPR Quantitative Structure-activity Relationships Skin Exposure Skin Permeability

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  North Carolina ; OSHA Region 4
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  224-232
• Volume:
  119
• Issue:
  1
• NIOSHTIC Number:
  nn:20053139
• Citation:
  Toxicol Sci 2011 Jan; 119(1):224-232
• Contact Point Address:
  Jim E. Riviere, Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606
• Email:
  jim_riviere@ncsu.edu
• Federal Fiscal Year:
  2011
• Performing Organization:
  North Carolina State University, Raleigh, North Carolina
• Peer Reviewed:
  True
• Start Date:
  20010601
• Source Full Name:
  Toxicological Sciences
• End Date:
  20100331
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:49820bbd86f7fe9db7e50960edc6666f1eb7a94c7d4db09da67ababac1b83102ecd8104f4d7bc7d3e8d941e6a2b5af5974f3af110d71a03135b4e8623e2a892d
• Download URL:
  https://stacks.cdc.gov/view/cdc/215956/cdc_215956_DS1.pdf
• File Type:
  [PDF - 362.17 KB ]