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Animal Models for Predicting Sensitization Potential . Judith C. Stadler Haskell Laboratory, DuPont Company Newark, DE. Dermal Sensitization. Regulatory Acceptance Guinea Pig Buehler Maximization Test Mouse Local Lymph Node Assay. Dermal Sensitization (continued). Other Tests

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animal models for predicting sensitization potential

Animal Models for Predicting Sensitization Potential

Judith C. Stadler

Haskell Laboratory, DuPont Company

Newark, DE

dermal sensitization
Dermal Sensitization
  • Regulatory Acceptance
    • Guinea Pig
      • Buehler
      • Maximization Test
    • Mouse
      • Local Lymph Node Assay
dermal sensitization continued
Dermal Sensitization (continued)
  • Other Tests
    • Guinea Pigs
      • Open Epicutaneous
      • Mauer Optimization Test
      • Split Adjuvant Technique
      • Freund’s Complete Adjuvant Test
      • Draize Sensitization
    • Mice
      • Mouse Ear Swelling Test
guinea pig tests
Guinea Pig Tests
  • Based on common principles
    • Chemical induction
    • Rest phase
    • Dermal Challenge
    • Skin Reaction Assessment
      • Erythema, edema,
guinea pig tests6
Guinea Pig Tests
  • Advantages
    • Measures skin reactions similar to human response
    • Large data base for comparison of many chemicals
    • Correlates well to human response
  • Disadvantages
    • Requires large numbers of animals
    • Subjective evaluation
    • Assessment of colored materials difficult
mouse local lymph node assay
Mouse Local Lymph Node Assay
  • Based on responses during induction rather than elicitation phase of sensitization
  • Measures induction of the T-lymphocyte proliferative response in skin draining lymph nodes
local lymph node assay
Local Lymph Node Assay
  • Sequence of Events
    • Topical application, generally to the ear
    • Epidermal cells release cytokines
    • Mobilize Langerhans’ cells
    • Antigen transported from skin to draining lymph nodes
    • Responsive T-cells activated and divide
    • Radioactivity incorporated during clonal expansion
local lymph node assay10
Local Lymph Node Assay
  • Advantages
    • Smaller numbers of animals required
    • Quantitative assay
    • Several doses can be evaluated
    • Colored materials can be assayed
  • Disadvantages
    • Insoluble or systemically toxic materials may not test well
    • Tests not predictive for metals
local lymph node assay regulatory status
Local Lymph Node AssayRegulatory Status
  • U.S. EPA has approved its use as a stand-alone assay
  • Europe has approved for registrations if the assay is positive. If the assay is negative, a follow-up guinea pig assay is required
    • This requirement expected to change by the end of 2000
respiratory sensitization
Respiratory Sensitization
  • No tests have been validated for regulatory testing
  • Use of animal models primarily for research and mechanistic studies
  • Evaluation of models for predictive assays continues
animal models of respiratory sensitization
Some use as predictive assays

Mouse

Guinea pig

Rat

Primarily used in asthma research

rabbit

dog

sheep

primate

Animal Models of Respiratory Sensitization
occupational respiratory allergic disorders
Occupational respiratory allergic disorders
  • Wide spectrum of disease
    • asthma
    • hypersensitivity pneumonitis
    • Pulmonary infiltrates with eosinophilia
    • Pulmonary institial fibrosis
  • Mechanisms
    • IgE, IgG4, cell-mediated immunity
  • Extent and duration of exposure related to likelihood of sensitization
guinea pig
Guinea pig
  • Similar to humans
    • Histaminic bronchoconstriction at antigen challenge
    • Exhibits airways hyperreactivity
    • Late-phase responses can be elicited
    • Lung eosinophilia
guinea pig use with chemical and protein workplace allergens
Guinea pig use with chemical and protein workplace allergens
  • Isocyanates
    • Various methods of induction
    • Inhalation challenge with chemical or the protein conjugates
  • Detergent enzymes
    • Inhalation induction model
    • Intratracheal test
guinea pig17
Guinea pig
  • Advantages
    • Ease of sensitization
    • Immunologically robust
    • Multifactorial
  • Disadvantages
    • IgG-dependent mechanism
    • Hyper eosinophilia
    • Dissociation between airway hyperreactivity and eosinophilia
    • Biological variability (outbred strains)
    • Cost prohibitive
mouse
Mouse
  • Similarities of the model to human
    • Influx of eosinophils and T-cells
    • histological features following acute exposures similar to human
      • Epithelial denudation
      • Interstitial airway edema
      • Thick basement membrane
      • Goblet cell hyperplasia
    • Mucus hypersecretions
    • Repeated exposure results in histological features of chronic asthma
mouse19
Mouse
  • Advantages
    • Molecular and immunological assays available
    • Acute bronchoconstriction and airway hyperreactivity can be elicited from antigen challenge
  • Disadvantages
    • Large doses required for antigen challenge
    • Difficult to measure eosinophil degranulation, rarely in airways
brown norway rat
Brown Norway Rat
  • Similarities to human sensitization
    • Serotonergic bronchoconstriction
    • IgE mediated
    • Early and late phase reactions
    • Airway hyperreactivity
    • Tissue + BAL accumulation of neutrophils, eosinophils, lymphocytes
brown norway rat21
Brown Norway Rat
  • Advantages
    • Good inflammatory responses
  • Disadvantages
    • Induction of airway hyperreactivity difficult
regulatory status
Regulatory Status
  • No one model has been validated for prediction of respiratory sensitization
  • New concerns may place higher priority on this area and encourage methods validation
    • Children’s Health issues
    • Food allergy
future direction
Future direction
  • Emphasis on structure-activity relationships
  • Assay development
    • molecular biology
    • other in vitro screening
references suggested reading
References/Suggested Reading
  • OECD Guidelines for the Testing of Chemicals 406 Skin Sensitisation (17-JUL-92)
  • OPPTS Health Effects Test Guidelines. OPPTS 870.2600 Skin Sensitization (5-AUG-98)
  • Dearman, R.J. D.A. Basketter, and I. Kimber (1999) Local lymph node assay: use in hazard and risk assessment REVIEW. J. Appl Toxicol. 19, 299-306.
  • Kimber, I, I.L. Bernstein, M.H. Karol, M.K. Robinson, K. Sarlo, and M.K. Selgrade (1996) Identification of respiratory allergens. Fund. and Appl Tox33, 1-10.
  • Padrid, Philip. Animal models of asthma. in Lung Biol. Health Dis. (1996), 96(Genetics of Asthma), 211-233.
  • Selig, William M.; Chapman, Richard W. Asthma. in In Vivo Models of Inflammation (1999), 111-135.