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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 l.jpg

Animal Models for Predicting Sensitization Potential

Judith C. Stadler

Haskell Laboratory, DuPont Company

Newark, DE


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Dermal Sensitization

  • Regulatory Acceptance

    • Guinea Pig

      • Buehler

      • Maximization Test

    • Mouse

      • Local Lymph Node Assay


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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


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Guinea Pig Tests

  • Based on common principles

    • Chemical induction

    • Rest phase

    • Dermal Challenge

    • Skin Reaction Assessment

      • Erythema, edema,


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Guinea Pig Tests


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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


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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


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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


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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


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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


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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


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Some use as predictive assays

Mouse

Guinea pig

Rat

Primarily used in asthma research

rabbit

dog

sheep

primate

Animal Models of Respiratory Sensitization


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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


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Guinea pig

  • Similar to humans

    • Histaminic bronchoconstriction at antigen challenge

    • Exhibits airways hyperreactivity

    • Late-phase responses can be elicited

    • Lung eosinophilia


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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


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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


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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


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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


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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


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Brown Norway Rat

  • Advantages

    • Good inflammatory responses

  • Disadvantages

    • Induction of airway hyperreactivity difficult


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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


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Future direction

  • Emphasis on structure-activity relationships

  • Assay development

    • molecular biology

    • other in vitro screening


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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.


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