ABSTRACT
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Origins and Progress in Immunotoxicity Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
The Tier-Testing Approach: Setting the Course for Modern Immunotoxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Use of Tier-Testing for Industrial and Environmental Chemicals . . . . . . 6 Adaptations of the Tier-Testing Approach . . . . . . . . . . . . . . . . . . . . . . . 6
The Emergence of Regulatory Guidance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Europe: Note for Guidance on Repeated Dose Toxicity . . . . . . . . . . . . . 8 United States: Guidance for Industry: Immunotoxicology Evaluation of Investigational New Drugs . . . . . . . . . . . . . . . . . . . 9 ICH S8: Immunotoxicology Studies for Human Pharmaceuticals . . . . . 9 Biologicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
The LLNA: A Concerted Effort to Validate Methodology . . . . . . . . . . . . . . . 10 Interpreting Laboratory Animal Data in Terms of Human Risk . . . . . . . . . . . . . . . . 11 Environmental and Wildlife Immunotoxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Developmental, Perinatal and Reproductive Immunotoxicology . . . . . . . . . . . . . . . 12 Next Trends in Immunotoxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Unintended Consequences of Therapeutic Immunomodulation . . . . . . . . . . . 12 Use of Transgenic Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 In Vitro Immunotoxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Application of Genomics Techniques as Tools for Hypothesis Generation and Mechanism of Action Studies . . . . . . . . . . . . . . . . . . . 14
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Disclaimer: This report has been reviewed by the Environmental Protection Agency’s Offi ce of Research and Development, and approved for publication. Approval does not signify that the contents refl ect the views of the Agency.
