Chemical Suppression And Susceptibility

Chemicals often suppress the developing immune system and its functional capabilities while affecting the adult system with less severity. When given during the maturation of the immune system, several well-known chemicals (e.g., TCDD, lead) are found to be more persistent immunosuppressants than when exposure occurs in adult life. Studies conducted to examine the toxic effects of chemical exposures on the developing immune system are limited (Holladay and Luster 1994).

Environmental agents can affect the immune system in various ways. Effects tend to include immunosuppression, possibly resulting in altered host resistance against infections or neoplastic agents; hypersensitivity or autoimmunity; and uncontrolled proliferation of immune components, i.e., lymphoma or leukemia. Quantification of T cell-dependent antibody responses is known to be an extremely reliable indicator of immunotoxicity and could very well be used to predict changes in host resistance as they develop (Luster et al. 2002).

Cell-mediated immunity (CMI) is considered more sensitive than humoral immunity when assessing appropriate endpoints for developmental immunotoxicity (DIT), although different responses are being measured (Holsapple 2002). Effects on CMI after prenatal or postnatal exposure include suppression of T-cell mitogen responses, skin graft rejection times, graft-versus-host reactivity, cytotoxic T lymphocyte (CTL) activity, and delayed hypersensitivity. Long-lasting postnatal impairment of CMI has been found after chemical exposure during development. Exposure to low levels of TCDD given to pregnant rats at both prenatal and postnatal time points results in severe thymic atrophy and cellular depletion in offspring (Holladay and Luster 1994).

Conceptually, a number of dynamic changes associated with the developing immune system could characterize critical windows for unique susceptibility of the immune system during its ontological development. Major benchmarks in the developing immune system that could potentially aid in the identification of critical exposure windows include: initiation of hematopoiesis; stem cell migration; progenitor cell expansion; thymus and bone marrow colonization; and establishment of immune memory (Dietert et al. 2000). Determinants of susceptibility include the following: exposure age, test species, strain, gender, and assessment age. Species differences in maturation times are variable; therefore, study designs must accommodate these differences to allow for extrapolation of animal data to humans.

The lack of standardization of both in vivo and in vitro models in current immunotoxicity studies has plagued the scientific community and its ability to measure toxic responses consistently. For example, the in vitro CTL assay to alloantigen is thought to be useful to determine developmental immunotoxicity status between 4-6 days after birth, whereas between 11-20 days of age, adult levels are reached (Holladay and Blaylock 2002). These data are useful when attempting to extrapolate laboratory animal or human clinical data to predict human disease from exposure scenarios, but the timing of exposure relative to immune development must be carefully considered. There are several examples of endpoints where this construct has been used to successfully establish human homology for adults, but not for juveniles (Dietert et al. 2000). Whole animal studies at this time are the most appropriate model to use when determining developmental alterations. In vitro testing allows for the characterization of a mode of action (MO A), and is often verified and linked with the results of in vivo experimentation. These methods, in conjunction with whole animal testing, allow data to be extrapolated from animals to humans at different stages of development. The following chemicals have been found to induce effects developmentally in both in vitro and in vivo assays.

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