Developmental immunotoxicity testing

Immune Function Assays Used in Developmental Immunotoxicity Testing..334... 

A recent workshop18 and forum19 addressed issues of the appropriate immune function methods and rodent species for evaluating developmental immunotoxicity. In both meetings the rat was identified as the preferred animal model for developmental immunotoxicity testing. This chapter will review evidence which implicates certain chemicals and drugs as being developmental immunotoxicants in rodents. 

IMMUNE FUNCTION ASSAYS EMPLOYED IN DEVELOPMENTAL IMMUNOTOXICITY TESTING... 

Holsapple, M.P. Developmental immunotoxicity testing A review. Toxicology, 185, 193, 2003. 

Developmental immunotoxicity testing has gained increasing attention with the recognition that for most drugs compared to date, when immunomodulatory effects are observed, the developing immune system is more sensitive than that of the adult. Therefore, safety limits for exposure of non-adults can be difficult to predict in the absence of age-relevant exposure assessment. 

As was the case with tier testing, developmental immunotoxicology has been driven by expert workshops to reach consensus on the most important issues three workshops were held in 2001 [79-81], and another in 2003 [82], These workshops contributed to the development of a proposed testing framework to detect developmental immunotoxicity, which is described in detail in chapter 21. 

Although chemical sensitization is a more complex process than immunosuppression, by far most of the efforts on developing in vitro assays are in this field. An important reason for this is that from the various fields of immunotoxicity, most of the animals are used for sensitization testing. In fact the number of animals required for sensitization is second only after developmental toxicity testing. 

Dietert RR, DeWitt J (2010) Developmental immunotoxicity (DIT) the why, when and how of DIT testing. In Dietert RR (ed) Immunotoxicity testing methods and protocols. Humana Press, New York, pp 17-26... 

Hypersensitivity and immunosuppression are considered the primary focus for developing in vitro methods in immunotoxicology. Nevertheless, in vitro assays to detect immunostimula-tion and autoimmunity are also needed. Although developmental immunotoxicity is an emerging concern, there are no in vitro test models available at this time. 

DeWitt JC, Peden-Adams MM, Keil DE, Dietert RR (2012) Current status of developmental immunotoxicity early-life patterns and testing. Toxicol Pathol 40 230-236... 

Collinge M, Burns-Naas LA, Chellman GJ, Kawabata TT, Komocsar WJ, Piccotti JR et al (2012) Developmental immunotoxicity (DIT) testing of pharmaceuticals current practices, state of the science, knowledge gaps, and recommendations. J Immunotoxicol 9 210-230... 

Dietert RR, Holsapple MP. Methodologies for developmental immunotoxicity (DIT) testing. Methods 2007 41 123-131. 

One advantage of rodents, beyond the exceptionally well-characterized immune system and availability of reagents, is the fact that DIT assessment may be able to be dovetailed into existing developmental and reproductive assessments. Certainly DIT testing using other mammalian species may be appropriate under some circumstances, but the opportunity to examine developmental immunotoxicity, developmental neurotoxicity, and reproductive toxicity using a common model suggests that the rodent is likely to remain the standard model of choice. This conclusion was also reached by various consensus panels (Holsapple et al., 2005). 

Holsapple MP, van der Laan JW, Van Loveren H. Developmental of a framework for developmental immunotoxicity (DIT) testing. In Immunotoxicology and Immuno-pharmacology, 3rd eds., edited by Luebke R, House R, Kimber I, pp. 347-361. Boca Raton, EL CRC Press, 2007. 

Methods for evaluating immunotoxicity in rodents are well established and are the basis of the ICH S8 guidance (ICH, 2006). Many of these methods have been adapted for use in developmental immunotoxicity studies in rodents (Dietert and Holsapple, 2007). Immunotoxicity testing in nonhuman primates, and in particular developmental immunotoxicity, has been requested by regulatory agencies for immunobiotherapeutics but the methods to date are not well established for nonhuman primates and vary to some extent from study to study. 

Short- to medium-term exposure has shown neurotoxicity, developmental toxicity, immunotoxicity, and endocrine disruption to be relevant end-points. Table 24 summarizes the critical studies for each compound and identifies NOAELs or LOAELs. The degree of each of the toxic end-points differs across the group as a whole. For example, tributyltin is well established as an aromatase inhibitor, and dibutyltin appears to have some potency also (exact characterization of the endocrine disrupting capacity of dibutyltin alone is difficult because of the presence of tributyltin as an impurity). Monobutyltin and mono- and dioctyltins have no aromatase inhibiting capacity in in vitro tests. No data are available for this end-point for the methyltins. 

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