A Practical Approach, Second Edition=Ronald D. Ho.pdf

POSTNATAL DEVELOPMENTAL MILESTONES 1097association between azathioprine and a slightly increased risk of nonspecific congenital anomaliesas well as prematurity (Penn et al., 1980), and another study described neonatal lymphopenia andthrombocytopenia in children following maternal azathioprine therapy (Davidson, 1994). No malformationshave been noted (Hou, 1999); but there have been reports of reduced birth weight andtransient neonatal immunocompromise (Jain, 1993; Laifer et al., 1994) following the use of tacrolimus,a cyclosporine-like immunosuppressant, during pregnancy. Taken together, the availableepidemiologic reports to date provide little evidence of increased malformations associated withthe use of clinical immunosuppressants during pregnancy, and the major risks appear to be adverseeffects on fetal growth and the fetal immune system following exposure to these agents during thesecond and third trimesters (Hendrickx et al., 2000).This discussion is relevant to subsequent decisions about how to test for adverse effects on thedeveloping immune system. Organs essential to the normal functioning of the immune system, likethe thymus or spleen or bone marrow, are not typically assessed in developmental and reproductivetoxicology (DART) studies, and this failure to assess developmental damage to the immune systemshould be reevaluated. The EPA has suggested that immune organs be weighed in rat pups beingculled from a standard two-generation reproductive toxicity study (OPPTS 870-3800). While thisis a logical first step, there is little rationale to support the predictive value of weighing neonatalimmune organs.In order to address this issue properly, it will be necessary to establish a more appropriate panelof tests to evaluate the effect of chemical toxicity on the developing immune system and to establishwhether or not critical windows of vulnerability to potentially immunotoxic compounds exist atspecific developmental stages in mammals. The primary conclusion from a recent workshop organizedby ILSI HESI was that the best approach to developmental immunotoxicology testing wasto address all of the ‘windows’ at once (e.g., using an exposure regimen that extended from earlygestation through lactation and weaning and into young adulthood), and then go back and dissectspecific windows if an effect is seen (Sandler, 2002; Holsapple, 2002b). Importantly, this approachhas the potential to distinguish between highly transient effects and those that are genuinelypersistent. This approach would also address the fact that the immune system continues to developpostnatally. This point is particularly relevant when rodents are used in studies because their immunesystem undergoes such considerable anatomical development after birth. However, an approachthat addresses all of the critical windows is also important in species where it is recognized thatthe immune system is essentially functional at birth. Even in humans, there is considerable developmentof functional competence during the neonatal period, and virtually the entire scope ofimmunological memory is established after birth.REFERENCESAhmad H. and Chapnick E.K. 1999. Conjugated polysaccharide vaccines. Infectious Disease Clinics of NorthAmerica. 13:113.Anderson, U., Bird, A.G., Britton, S. and Palacios, R. 1981. Humoral and cellular immunity in humans studiedat the cell level from birth to two years of age. Immunol. Rev., 57:1.Aspinall, R., Kampinga, J. and Bogaerde, J. 1991. T cell development in the fetus and the invariant hypothesis.Immunol. Today, 12:7.August, C.S., Berkel, A.I., Driscoll, S. and Merler, E. 1971. Onset of lymphocyte function in the developinghuman fetus. Ped. Res., 5:539.Barnett, J.B. 1996. Developmental Immunotoxicology. In: Experimental Immunotoxicology. (Smialowicz, R.J.and Holsapple, M.P., eds.) CRC Press, Boca Raton, FL. Pg. 47.Barrett D.S., Rayfield L.S. and Brent L. 1982. Suppression of natural cell-mediated cytotoxicity in man bymaternal and neonatal serum. Clin. Exp. Immunol., 47: 742.Berry S.M., Fine N., Bichalski J.A., Cotton D.B, Dombrowski M.P. and Kaplan J. 1992. Circulating lymphocytesubsets in second- and third-trimester fetuses: comparison with newborns and adults. Am. J. Obstet.Gynecol., 167: 895.© 2006 by Taylor & Francis Group, LLC