Perinatal Immunotoxicity: Why Adult Exposure Assessment Fails to Predict Risk

Abstract

Recent research has pointed to the developing immune system as a remarkably sensitive toxicologic target for environmental chemicals and drugs. In fact, the perinatal period before and just after birth is replete with dynamic immune changes, many of which do not occur in adults. These include not only the basic maturation and distribution of immune cell types and selection against autoreactive lymphocytes but also changes designed specifically to protect the pregnancy against immune-mediated miscarriage. The newborn is then faced with critical immune maturational adjustments to achieve an immune balance necessary to combat myriad childhood and later-life diseases. All these processes set the fetus and neonate completely apart from the adult regarding immunotoxicologic risk. Yet for decades, safety evaluation has relied almost exclusively upon exposure of the adult immune system to predict perinatal immune risk. Recent workshops and forums have suggested a benefit in employing alternative exposures that include exposure throughout early life stages. However, issues remain concerning when and where such applications might be required. In this review we discuss the reasons why immunotoxic assessment is important for current childhood diseases and why adult exposure assessment cannot predict the effect of xenobiotics on the developing immune system. It also provides examples of developmental immunotoxicants where age-based risk appears to differ. Finally, it stresses the need to replace adult exposure assessment for immune evaluation with protocols that can protect the developing immune system.

Developmental immunotoxicity (DIT) testing of pharmaceuticals: Current practices, state of the science, knowledge gaps, and recommendations

“…There are a number of examples in the recent literature suggesting that the developing immune system is more sensitive than that of the adult for some immunotoxic alterations (Miller et al, 1998;Dietert et al, 2003;Dietert and Piepenbrink, 2006;Luebke et al, 2006). This apparent sensitivity may be due in part to novel immune maturation events including the need for rapid perinatal changes in functional equilibrium to restore the critical immune balance between T-helper (T H )-1 and T H 2 cell populations through the enhancement of T H 1 capacity in the newborn (Holt et al, 2005;Yun and Lee, 2005).…”

“…Although significant progress has been made to characterize immune system development across species (reviewed in Holsapple et al, 2003;Dietert and Piepenbrink, 2006;Burns-Naas et al, 2008), many gaps in understanding remain. Further evaluations of agerelated changes in immune system structure, phenotype, and function must be conducted both within a species and across species.…”

“…Five critical windows of vulnerability in the development of the immune system have been described, and the timing of these critical windows compared in rodents and humans , but it is unclear how the timing of these critical windows compares across other non-clinical species. In addition, seven events that are either completely unique to the developing immune system (i.e., they lack equivalents in the adult immune system) or play a unique role in the developing immune system have been described (Dietert and Piepenbrink, 2006), but it is not entirely transparent within which critical window(s) each of these seven events fall. Our lack of understanding challenges our ability to rationally design studies that will identify risks to specific stages of human immune system development.…”

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

“…This approach of carving up development into distinct segments, or boxes, for direct sensitivity testing would seem to offer advantages that are not restricted solely to the immune system. Recently, additional developmental immune windows have been described that emphasize heightened perinatal susceptibilities (Dietert & Piepenbrink, 2005). Exposure to a low level of an immunotoxicant during these different immune developmental windows might be expected to produce different outcomes.…”

“…T cell-dependent functions are frequently impaired, and these alterations may be more persistent than with similar adult toxicant exposure (Dietert et al, 2003;Luebke et al, 2004). The heightened sensitivity of T cell-dependent function to early-life immunotoxicant exposure may be linked to the dramatic reversal of T helper balance and changes in dendritic cell maturation that occur before and after birth (reviewed in Dietert & Piepenbrink, 2005). This can lead to increased susceptibility to both infectious diseases and cancer.…”