Immunotoxicity assessing immune function

While profound immunosuppression can lead to an increased incidence of infectious or neoplastic diseases, interpreting data from experimental immunotoxicology studies or epidemiological studies for quantitative risk assessment purposes can be problematic. This is because inadvertent exposures to immunotoxic agents may often be expressed as a mild-to-moderate change, reflected, for example, by a 15 to 25% decrement in an immune parameter compared to control values. To help address the clinical consequences of mild-to-moderate immunosuppression, we examined available experimental, clinical and epidemiological studies that examined the association between suppression of immune function and infectious disease, independent of the etiology of suppression. 

While changes in cell phenotypes have proved useful in some settings to characterize the immunotoxicity of xenobiotics,1 phenotypic analysis alone is often not a sensitive indicator of low dose immunotoxicity for many agents that alter immune function. Xenobiotics that exert selective toxicity on lymphoid and myeloid cells may be discovered through immunophenotypic analysis. However, most agents produce immunotoxicity at doses much lower than those required to produce cytotoxicity or interfere with primary lymphoid organ differentiation. Some of the most potent immunosuppressive chemicals that have been tested, such as cyclosporine A, do not alter immunophenotype at doses that are immunosuppressive. On the other hand, when phenotyping is linked to assessment of functional parameters of the cells, immunotoxic effects are more likely to be identified. 

The impacts of contaminants on the structure of the immune system can be assessed by examining white blood cell (WBC) numbers and the mass and cellularity of immune organs, although these indicators are usually not as sensitive as measures of immune function. Avian immunotoxicity studies frequently assess total and (or) differential WBC counts [79], and immunosuppression can be indicated by reduced numbers of WBCs or elevated WBC numbers caused by recurrent infections. An elevated heterophil to lymphocyte ratio can indicate altered immune status in response to corticosteroid stress hormones or other factors [78,7 9], Exposure to lead shot or lead acetate has been shown to alter total and (or) differential WBC numbers in Japanese quail (Coturnix coturnix) and mallards [81-83], In western grebes (Aechmophorus occidentalis) from California, concentrations of mercury in the kidney were positively correlated with heterophil... 

Immunotoxicity. No immunological effects were reported in case studies of human exposure. There was a decrease in spleen weight in rats orally exposed to p-cresol for 90 days (MBA 1988b), which, although unaccompanied by histopathological changes, suggests the possibility that cresols may affect the immune system. A battery of immune function tests would better enable assessment of the immunotoxicity of cresols in humans and animals. 

Immunological Effects. Histopathologic evaluations in animals suggest that chlorobenzene may be immunotoxic however, direct tests of immune function have not been performed. In the absence of functional assessment, the potential for chlorobenzene to affect the immune system in humans can not be determined. 

Immunotoxicity. There are no data available on the immunotoxicity of chlorobenzene in humans by any route of exposure. Histological examination of organs and tissues of the immunological system in mice and rats provide some evidence that chlorobenzene is potentially immunotoxic. Immune function tests would provide a better assessment of potential immunotoxic effects in humans. 

The human data suggest that the immune system is a target of white phosphorus toxicity however, no information on the potential of white phosphorus to impair immune function is available. Animal studies assessing the results of a battery of immune function tests could be useful in determining the immunotoxic potential of white phosphorus. Information on different routes of exposure could be useful in assessing if effects are route specific. 

Immunotoxicology Evaluation of IND (PDF) (Issued October 2002, Posted October 31,2002).This guidance makes recommendations to sponsors of INDs on (1) the parameters that should be routinely assessed in toxicology studies to determine the effects of a drug on immune function (2) when additional immunotoxicity studies should be conducted and (3) when additional mechanistic information could help characterize the significance of a given drug s effect on the immune system. 

Figure 3.3.1-2 Application of the TDAR assay in immunotoxicity assessment. When evaluating unintended immunosuppression, the TDAR assay may be conducted when evidence of immunotoxicity is seen in repeated-dose toxicity studies. In these instances, the assay should be conducted prior to Phase 3 or earlier, depending on factors such as the severity of the findings and the intended patient population. The TDAR assay also could be used early in the drug development process to screen for immunotoxicity potential. This approach may be useful particularly to help de-risk unintended off-target immunomodulation or when a novel target/mechanisms may alter immune function.

Evaluation of Phagocyte Activity. As mentioned above, the ICH S8 guidance on immunotoxicity testing calls for follow-up testing as necessary. If it is determined that follow-up testing is required and the cell types affected in the initial evaluation of a test article are not involved in the more general assay for immune function (the T-Dependent Antibody Response Assay), specihc assays may be conducted to assess the function of a particular cell type such as... 

In addition to their active compounds, pesticide formulations often contain by-products of the manufacturing process and a quantity of inert ingredients. The potential contribution made by all known or potential additional components in any pesticide preparation must be considered in assessment of a pesticide for immunotoxic potential. For example, 0,0,S-trimethyl phosphorothioate (OOS-TMP), a contaminant of malathion, has been shown to alter immune function (19,... 

Immunotoxicity. The results from the available human and animal studies indicate that di- -butyl phthalate is not a skin-sensitizing agent following dermal exposure (Lehman 1955 Schulsinger and Mollgaard 1980). These studies did not assess other aspects of immunotoxicity. Additionally, immunotoxicity has not been adequately assessed following inhalation or oral exposure. Tests of several additional end points of humoral and cell-mediated immune function are needed to assess the sensitivity of this system to di- -butyl phthalate. 

Spanhaak, S. (2006). The ICH S8 immnnotoxicity guidance. Immune function assessment and toxicological pathology autonomous or synergistic methods to predict immunotoxicity Experimental and Toxicologic Pathology, 57, 373-376. 

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