Systematic Application of Mode-of-Action and Human Relevance Analysis: Styrene-Induced Lung Tumors in Mice

Details

• Personal Author:
  Frank EA ; Meek B
• Description:
  Risk assessment of human health hazards often relies on observations from animal experiments. Although exposure studies in rats and mice are a major basis for determining risk in many cases, observations made in animals do not always reflect health hazards in humans due to differences in biology. In this critical review, the mode-of-action (MOA) human relevance framework was used to assess the likelihood that bronchiolar lung tumors observed in mice chronically exposed to styrene represent a plausible tumor risk in humans. Available datasets were used to determine the weight-of-evidence 1) that styrene-induced tumors in mice occur through a MOA initiated by metabolism of styrene by Cyp2F2; and 2) whether the hypothesized key event relationships are plausible in other species. Analysis of data using five modified Hill causality considerations indicated that the hypothesized Cyp2F2-dependent MOA is active in mice, but only results in tumorigenicity in susceptible strains. Assessment of species concordance to determine whether analogous key event relationships do or could plausibly occur in other species concluded that while some of the proposed key events are biologically plausible in rats, the MOA is improbable in humans due to poor concordance of both early and late key events reflecting key differences in airway biology and physiology. This analysis serves as a rigorous demonstration of the framework's utility in increasing transparency and consistency in evidence-based assessment of MOA hypotheses in toxicological models and determining relevance to human health. [Description provided by NIOSH]
• Subjects:
  Animals Neoplasms Occupational Health Safety Styrene Toxicology
• Keywords:
  Animal Studies Biological Effects Risk Assessment Tumors
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Ohio ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  DSI - Division of Science Integration
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  192
• NIOSHTIC Number:
  nn:20067220
• Citation:
  Toxicologist 2023 Mar; 192(S1):278
• CAS Registry Number:
  Styrene (CAS RN 100-42-5)
• Federal Fiscal Year:
  2023
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 62nd Annual Meeting & ToxExpo, March 19-23, 2023, Nashville, Tennessee
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:82947c4872248b5814ff15bd9c1e076407d2deeadb23a9b49f2d26fd0f1d009850c4d94e77c636021b6dce46840d5589ff5c9ab597397361eda73366952433ea
• Download URL:
  https://stacks.cdc.gov/view/cdc/231347/cdc_231347_DS1.pdf
• File Type:
  [PDF - 1.09 MB ]