Immunotoxicity studies assessments

Anonymous, Report of validation study of assessment of direct immunotoxicity in the rat. The ICICIS Group Investigators. International Collaborative Immunotoxicity Study, Toxicology, 125, 183, 1998. 

Follow-on studies are also recommended as needed. These include determination of potential test article effects on blood or tissue immunophenotypes (by flow cytometry or immunohistochemistry), natural killer cell, macrophage, or neutrophil function, host resistance to infection or tumors, and cell-mediated immunity. The important issue in all of these guidelines is this do not ignore signs of immunotoxicity, and assess these findings when observed. 

Flow cytometry is now commonly used in immunotoxicity studies to assess changes in relative frequency and number of lymphoid and myeloid cells in the spleen, lymph nodes, bone marrow and/or peripheral blood of rodents, and in the peripheral blood of humans. A list of selected cell surface markers useful in immunotoxicity studies is shown in Table 7.3. Notably, the majority of available reagents are specific for murine antigens with human reagent availability a close second. Reagents for rat, primate, and... 

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. Studies that assess the potential effects of radium on the immune system of orally or dermally exposed humans have not been located. The case report of a chemist exposed to radium primarily via inhalation for 14 years reported leukopenia and the almost total absence of granular leukocytes, leukoblastic groups, and lymphoid tissue in the bone marrow. No studies on animals exposed via inhalation, oral, or dermal routes have been located. A study reporting a reduction in peripheral white blood cells in intraperitoneally injected rats has been located. The reported observations suggest that immunological effects may be a concern for humans exposed to radium. 

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. 

The scope of the toxicity studies when surrogate molecules have been used includes pharmacology studies, subchronic and chronic studies, reproductive toxicity studies, immunotoxicity studies, and even carcinogenicity studies. Short-term assays like safety pharmacology studies are too short for there to be an antisense effect, so we have not used the surrogate approach in these assays. However, when safety pharmacology endpoints are included in subchronic or chronic studies, surrogates are assessed. 

Immunotoxicity. No information is available on the immunotoxic effects of 1,1-dichloroethane in humans or animals. Immunotoxicity studies in animals, particularly by the inhalation route since this is the most likely route of human exposure, would be useful to assess the potential risk for... 

Cellular immunity protects against intracellular bacteria, viruses and cancer, and is mediated by antigen-specific memory T lymphocytes. DTH is a measure of cellular immunity that relies on the generation of antigen (Ag)-specific memory T cells, which upon subsequent encounter with Ag, become activated, release inflammatory mediators, migrate, and recruit other cell types to the site of contact. The result is an inflammatory reaction and tissue injury. DTH can only be transferred from sensitized to normal individuals via lymphocytes (thus ce//-mediated), not humorally (Ig-mediated), and often takes several days to develop. Thus, the study of DTH (as a follow-on when the weight-of-evidence review indicates additional immunotoxicity studies are warranted) in nonclinical immunotoxicity risk assessment can be a useful predictor of effects on cell-mediated immunity. 

Many of the end points that have been validated for use in rodent immunotoxicity (ICH, 2006) assessment have been adapted for use in developmental immunotoxicity studies in nonhuman primates (Buse et al., 2003). 

There is an obvious need for running dedicated clinical immunotoxicity studies. Indeed, one of the major hmitations of current immunotoxicity evaluation is the lack of human data. Risk is therefore assessed largely on the basis of preclinical studies, but the suitability and predictability of animal findings is at best debatable. 

Some animal studies indicate that dietary exposure to methyl parathion causes decreased humoral and cellular responses (Shtenberg and Dzhunusova 1968 Street and Sharma 1975). A more recent, well-designed animal study that included a battery of immuno/lymphoreticular end points showed few effects at the nonneurotoxic doses tested (Crittenden et al. 1998). No adequate studies are available in humans to assess the immunotoxic potential of methyl parathion. Therefore, studies measuring specific immunologic parameters in occupationally exposed populations are needed to provide useful information. Further studies are also needed to investigate the mechanism for methyl parathion-induced immunotoxicity since this information would help to identify special populations at risk for such effects. 

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. 

Vos, J.G., Immunotoxicity assessment Screening and function studies, Arch. Toxicol., S4, 95, 1980. 

SOT sunset session Developmental toxicology Issues with including neurotox and immunotox assessments in reproductive toxicology studies. New Orleans, LA March, 2005... 

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