Immunotoxic Mixtures

The study of immunotoxic mixtures is complicated by the large number and diversity of chemicals agents that are toxic to the immune system, multiple mechanisms by which the immune system is impacted, and exposures that are almost always to mixtures containing numerous immunotoxins. 

Many persistent organic pollutants (POPs) and other environmental contaminants have been associated with immunotoxic effects, but, in most instances, it remains difficult to assign the effects to pure compounds. For example, immunotoxic effects of PCBs in free-ranging harbor seals have been associated with increasing blubber concentrations of PCBsJ34 yet the waters inhabited by these animals are also contaminated with other POPs, including chlorinated pesticides and chlorinated polynuclear aromatic hydrocarbons. Indeed, the PCBs themselves are mixtures of different moieties with varying immunotoxic properties. 

Several studies, however, have been able to demonstrate the immunotoxic effects of mixtures. Illustrative examples of these follow. 

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Silkworth JB et al Immunotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in a complex environmental mixture from the... 

Organic solvents, which induce CYP2E1, are comprised of a few broad chemical classes, including hydrocarbons such as benzene and toluene, halogenated aliphatic compounds such as carbon tetrachloride and dichloroethane, aliphatic alcohols such as ethanol, and hydroxyethers such as 2-methoxyethanol. Industrial solvents are frequently mixtures of several compounds. The most frequent solvent-associated toxicity occurs from occupational exposure. A number of organic solvents have been examined for their effects on the immune system, and the requirement for their bioactivation to produce immunotoxicity has been well established. 

The immunotoxic potential of the PBDE mixture Bromkal 70-5 DE was compared to the technical PCB mixture Aroclor 1254 and the potential of the single congener 2,2, 4,4 -tetraBDE to that of 2,3,3, 4,4 -pentachlorobiphenyl (CB-105) in rats and mice. In mice, all compounds were immunotoxic, but in rats only the PCBs. This points to the existence of a considerable range of species differences [95],... 

An immunotoxicology study showed that co-exposure to a mixture of benzene (2.13) and toluene (2.73) resulted in the enhancement of the immunotoxic effects of benzene. The authors surmised that toluene competed with benzene for Phase I metabolizing enzymes, thereby causing benzene concentrations in the body to be higher than if benzene were present alone. 42 ... 

Dibutyltin dichloride (DBTC) is a widespread environmental pollutant that exhibits developmental toxicity in animals 19 and immunotoxic effects in human cells in vitroJ2°l No studies were found in the literature that compared the developmental and immunotoxic effects of DBTC alone to a mixture of DBTC and ethanol. One study, however, found that ethanol co-administered with DBTC increased the toxicity of DBTC in the liver and pancreas of laboratory animals both acutely and chronically. 21 An analysis of this study suggests that the combination of DBTC and ethanol might be expected to show enhanced toxic effects on other body organs and systems. 

Immunotoxic chemicals can interfere with the body s ability to ward off disease, can induce and exacerbate allergic responses, and contribute to autoimmune diseases. The complexity of the immune system and its interaction with other body systems makes it particularly vulnerable to attack by xenobiotics. Studies that have been carried out, however, have demonstrated that a wide variety of chemicals are immunotoxic and that chemical mixtures such as those contained in air polluted with the products of combustion, industrial emissions, and tobacco smoke is immunotoxic. Such polluted air can induce immunostimulative responses and bring on allergic reactions in previously sensitized individuals. 

Sanchez-Dardon, J., I. Voccia, A. Hontela, P. Anderson, P. Brousseau, B. Blakely, H. Boermans and M. Fournier. Immunotoxicity of cadmium, zinc and mercury after in vivo exposure, alone or in mixture in rainbow trout (Oncorhynchus mykiss). Dev. Comp. Immunol. 21 133 1997. 

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). 

Oral studies of Aroclor mixtures in monkeys confirm the findings of immunotoxicity in the other species and further indicate that the immune system of monkeys is particularly sensitive to PCBs. 

In induced models, a susceptible animal strain is immunized with a mixture of an adjuvant and an autoantigen isolated from the target organ. Examples are adjuvant arthritis in the Lewis strain rat (Pearson, 1956) and experimental allergic encephalomyelitis, a model of multiple sclerosis (Ben-Nun Cohen, 1982). Induced models are often used to study the pathogenesis of and therapeutic venues for relevant autoimmune diseases. These models have been proposed as means to evaluate the immunomodulatory effects of chemicals on ongoing autoimmune diseases in a second tier of immunotoxicity testing. 

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