Immunotoxicity studies

Institoris L, Siroki O, Desi I. 1995. Immunotoxicity study of repeated small doses of dimethoate and methyl parathion administered to rats over three generations. Hum Exp Toxicol 14 879-883. 

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. 

Food and Drug Administration, HHS, International Conference on Harmonisation Guidance on S8 Immunotoxicity Studies for Human Pharmaceuticals availability. Notice, Fed. Regist., 71, 19193,2006. 

ICH Harmonised Tripartite Guideline, Immunotoxicity Studies for Human Pharmaceuticals (S8) (http //www.ich.org/, 2005). 

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... 

The immunotoxicity study will provide information on suppression of the immune system, which might occur as a result of repeated exposure to a test chemical. The protocol for the US-EPA OPPTS test guideline is intended to be used along with data from routine toxicity testing, to provide more accurate information on risk to the immune system. See also Section 4.7.6. 

Immunotoxicity. Reports of immunotoxicity are restricted to the findings of treatment-related altered thymus and spleen weights in animals exposed to chlorine dioxide or chlorite (Daniel et al. 1990 Gill et al. 2000 Harrington et al. 1995a). Neither chlorine dioxide nor chlorite appear to be of particular immunotoxicity concern. Additional immunotoxicity studies do not appear to be needed at this time. 

Roth, D.R., Roman, D., Ulrich, P., Mahl, A., Junker, U. and Perentes, E. (2006) Design and evaluation of immunotoxicity studies. Experimental and Toxicologic Pathology, 57, 367-371. 

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. 

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. 

ICH S8. Immunotoxicity Studies for Human Pharmaceuticals. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 15 September 2005. 

Methods include standard toxicity studies and additional immunotoxicity studies conducted as appropriate. Whether additional immunotoxicity studies are appropriate should be determined by a weight of evidence review. 

Considerations for developmental toxicity studies for preventive and therapeutic vaccines for infectious disease indications Nonclinical safety evaluation of pediatric drug products Nonclinical safety evaluation of drug and biological combinations Immunotoxicity studies for human pharmaceuticals (ICH S8)... 

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. 

---