Fetal and early postnatal life represent critical periods in vertebrate immune system development. Disruption of such development by perinatal immunotoxic chemical exposure has been widely described in experimental animal models. The resultant inhibited postnatal immune responses in such animals are often more dramatic and persistent than those after exposure during adult life. Further, recent reports suggest that prenatal exposure to immunotoxicants may exacerbate postnatal aberrant immune responses (e.g., hypersensitivity disorders and autoimmune disease) in genetically predisposed rodents. Limited information is available regarding the possibility of inhibited postnatal immune capacity in humans as a result of developmental immunotoxicant exposure. The multifactorial nature of hypersensitivity and autoimmune responses will further complicate the elucidation of possible relationships between chemical exposure during ontogeny of the human immune system and immune-mediated disease later in life. Taken together, however, the available animal data suggest the potential for altered postnatal immune function in humans exposed to immunotoxicants (e.g., environmental chemicals and therapeutic agents) during fetal and/or early postnatal life.

Fetuses, infants, and juveniles (preadults) should not be considered simply "small adults" when it comes to toxicological risk. We present specific examples of developmental toxicants that are more toxic to children than to adults, focusing on effects on the immune and respiratory systems. We describe differences in both the pharmacokinetics of the developing immune and respiratory systems as well as changes in target organ sensitivities to toxicants. Differential windows of vulnerability during development are identified in the context of available animal models. We provide specific approaches to directly investigate differential windows of vulnerability. These approaches are based on fundamental developmental biology and the existence of discrete developmental processes within the immune and respiratory systems. The processes are likely to influence differential developmental susceptibility to toxicants, resulting in lifelong toxicological changes. We also provide a template for comparative research. Finally, we discuss the application of these data to risk assessment.

was published in 1993 (NAS, 1993). Among the recommenand evaluated for changes to the immune system and for reproducdations were changes in the risk assessment process, changes tive toxicity. Dose-dependent amounts of MXC and metabolites were present in milk and plasma of dams and pups. The high dose in surveillance of the food supply, and a call for better inforof MXC reduced litter size by É17%. Ano-genital distance was mation on the effects of pesticides on the developing aniunchanged, although vaginal opening was accelerated in all mals' reproductive, immune, and central nervous systems. treated groups, and male prepuce separation was delayed at the The National Toxicology Program, in conjunction with middle and high doses by 8 and 34 days, respectively. In the collaborators at EPA's National Health and Environmental neurobehavioral evaluation, high-dose males were more excitable, Effects Research Laboratory, developed a design that would but other changes were inconsistent and insubstantial. A decrease address some of the data needs identified in the NAS report. in the antibody plaque-forming cell response was seen in malesThe NAS report identified the exposure period of concern only. Adult estrous cyclicity was disrupted at 50 and 150MXC, for humans as being from the last trimester of pregnancy to doses which also showed reduced rates of pregnancy and delivery. years of age, a range that is approximated in the rodentUterine weights (corrected for pregnancy) were reduced in all study used here. Because the concern was on direct contreated pregnant females. High-dose males impregnated fewer untreated females; epididymal sperm count and testis weight were sumption of pesticide residues, we dosed dams for the week before and the week after birth, and then direct-dosed the pups from postnatal day (pnd)7 to pnd42, the approximate This article has been reviewed by the National Health and Environmental age of puberty in these rats. Animals are taken at various Effects Laboratory, U.S. Environmental Protection Agency, and approved points in the dosing period to ascertain effects: compound for publication. Approval does not signify that the contents necessarily in milk is determined at pnd7, the last day of dosing for the reflect the views of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.dam, and the time during her dosing when she is likely to 138

Fetuses, infants, and juveniles (preadults) should not be considered simply "small adults" when it comes to toxicological risk. We present specific examples of developmental toxicants that are more toxic to children than to adults, focusing on effects on the immune and respiratory systems. We describe differences in both the pharmacokinetics of the developing immune and respiratory systems as well as changes in target organ sensitivities to toxicants. Differential windows of vulnerability during development are identified in the context of available animal models. We provide specific approaches to directly investigate differential windows of vulnerability. These approaches are based on fundamental developmental biology and the existence of discrete developmental processes within the immune and respiratory systems. The processes are likely to influence differential developmental susceptibility to toxicants, resulting in lifelong toxicological changes. We also provide a template for comparative research. Finally, we discuss the application of these data to risk assessment.