Immunotoxicity animal models

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. 

Use of in vivo Tests. In vivo tests are more relevant indicators than are in vitro tests of immunotoxicity since the dynamic interactions between the various immuno-components, as well as the pertinent pharmacokinetic (absorption, distribution, plasma concentrations) and metabolic factors, are taken into consideration. However, it is important to select the appropriate animal model and to design the protocol such that it will accurately reflect drug (or relevant metabolite) exposure to humans. For example, one should consider species variability when selecting the animal model, since biological diversity may further obscure the ability to accurately predict human toxicity. 

Two organochlorine pesticides have also been evaluated in animal models using early life stage exposures. Methoxychlor (Chapin et al., 1997) and heptachlor (Smialowicz et al., 2001) were evaluated for immunotoxicity after perinatal plus juvenile exposure of rats. In the case of methoxychlor, T cell-dependent antibody responses were depressed persistently in males but not females (Chapin et al., 1997). For heptachlor, early exposure of Sprague-Dawley rats, using doses relevant to human exposure, produced persistent impairment of antibody responses in males but not females. No adult-exposure immunotoxicity was observed at the doses examined, suggesting that there is an increased susceptibility of the prenatal and/or early postnatal life stages to this pesticide (Smialowicz et al., 2001 Smialowicz, 2002). 

Immunotoxicity testing in various animal models is common for biologies because of their immunomodulatory nature. Since most biopharmaceuticals... 

A number of animal models have been developed and validated to detect the chemical-induced direct immunotoxicity. Several compounds, including certain dmgs, have been shown in this way to cause immunosuppression or skin allergic responses. In this chapter, the various mechanisms of immimotoxicity are discussed by which a compound affects different cell types and interferes with immune responses, ultimately leading to immunotoxicity as well as sensitizing capacity. 

Autoimmunity is much more complex than hypersensitivity. Animal models exist for many autoimmune conditions, and autoimmunity has been clearly demonstrated in humans, although it is a relatively infrequent occurrence. Therefore, the existence of autoimmune disease and the expected consequences cannot be denied. However, the ability of drugs and chemicals to exacerbate or trigger autoimmune disease in either animal models or humans is poorly understood. In fact, of all the possible consequences of immunotoxicity, autoimmunity is unquestionably the least understood. Primarily... 

One of the obvious and most important goals of an experimental immunotoxicity testing strategy is to enable the best extrapolations between the results generated in the animal models and the potential risk of immunotoxicity in humans. One of the recent fallouts of this goal has been the recognition that the historic approaches that have been used in clinical... 

Zelikoff, J.T., D. Bowser, K.S. Squibb and K. Frenkel. Immunotoxicity of low level cadmium exposure in fish an alternative animal model for immunotoxicological studies. J. Toxicol. Environ. Health 45 235-248, 1995. 

Commercial PCB Mixtures. Information on the immunotoxicity of commercial PCBs in orally-exposed animals is available from intermediate- and chronic-duration studies in various species. Findings in nonhuman primates are emphasized in the following summary because monkeys appear to be more sensitive than other species and provide a better animal model due to phylogenetic and biologic similarities to humans (Tryphonas 1994, 1995). 

Chapter 4.2 Application of Flow Cytometry in Drug Development Chapter 10.1 Alternative Animal Models for Immunomodulation and Immunotoxicity... 

The target organs and mode of action of OTC have been discussed and can be summarized as follows the most toxic compounds tetramethyltin (TMT) and tetraethyltin (TET) are highly neurotoxic in mammals there is evidence for the hepatotoxicity of DBT in animal models the butyltin and TPhT compounds have been shown to be immunotoxic in mammals TPT is classed by the US Environmental Protection Agency as a probable human carcinogen there is some evidence that TPT exhibits endocrine-disrupting properties in rats and the butyltin compounds exhibit teratogenic effects in mammals. However, it is very apparent from reviews in the area that the chronic effects of the widely dispersed butyltin compounds have not been studied in detail and their effects on humans are consequently not well understood. 

Three studies have noted embryonic Pb immunotoxicity in Cornell K strain white Leghorn chickens. This testing animal model has the virtue of relatively high-throughput exposure studies at a multiplicity of embryonic time windows (Hussain et al., 2005 Lee and Dietert, 2003 Lee et al., 2001). Lead exposure at E12 with 400 xg per egg resulted in decreased production of IFN cytokine and reduced DTH. Chickens exposed to Pb at 5—400 p.g per egg and at E5, E7, E9, or E12 embryological time points showed suppressed IFN and NO production at the first three exposure time points at 5—6 weeks of age. DTH was unaltered. Hussain et al. (2005) evaluated the... 

Polycyclic aromatic hydrocarbons are potent immunosuppressive environmental contaminants. Immunotoxic effects of PAHs, which may contribute to their carcinogenic potential, have been established in various animal models and in human immune cells (van Grevenynghe et al., 2004). Inhibition of the production of immunocompetent cells (lymphocytes and monocytes) is likely one of the mechanisms contributing to the immunosuppression due to PAHs. Exposure to PAHs inhibits the differentiation of monocytes into dendritic cells and macrophages it also induces apoptosis of both pre-T cells in the thymus and pre-B cells in the bone marrow, which may account for thymic atrophy and decreased lymphoid cell recovery from the spleen, lymph nodes, and bone marrow in PAH-exposed mice (Lutz et al., 1998 Page et al., 2002). These toxic effects towards precursors of immune cells have been linked, at least in part, to the PAHs metabolism into toxic reactive intermediates triggering apoptosis of pre-B eells (Mann et al., 1999). 

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