Developmental Immunotoxicity (DIT) in Drug Safety Testing: Matching DIT Testing to Adverse Outcomes and Childhood Disease Risk
Rodney R. Dietert.
Developmental immunotoxicity (DIT) recently emerged as a significant concern for drug safety and was the topic of several recent scientific forums in Europe, North America and Asia. The heightened concern is based on several observations: 1) many childhood diseases with recent increases in prevalence, such as asthma, allergic disease, leukemia and certain infections, have clear linkages to the immune system and immune dysfunction, 2) the developing immune system has been shown to be a particularly sensitive target for xenobiotic-induced adverse outcomes, 3) immunotoxicity assessment following adult exposure to xenobiotics is ineffective for predicting immunotoxic risk in the non-adult and 4) in several cases developmental immunotoxicity to low-level xenobiotic exposure can take the form of immune dysfunction in the absence of readily detected morphometric/histological alterations. The present review examines harmonized preclinical drug safety guidelines for immunotoxicity in light of environmentally-mediated childhood disease trends as well as research-based mechanisms for DIT. Because none of the guidelines was designed to address risk of DIT, suggestions are offered for closing the early-life immune dysfunction data gap. A longer-term goal is to help narrow the difference between current guideline expectations and the known sensitivity of the developing immune system for potential adverse outcomes.
Keywords: Developmental immunotoxicity (DIT), immune dysfunction, pediatric drug safety, allergic disease, autoimmunity, host resistance
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