Development of a testing battery to assess chemical-induced immunotoxicity: National toxicology program's guidelines for immunotoxicity evaluation in mice

Luster, Michael I.; Munson, Albert E.; Thomas, Peter T.; Holsapple, Michael P.; Fenters, James D.; White, Kimber L.; Lauer, Lloyd D.; Germolec, Dori R.; Rosenthal, Gary J.; Dean, Jack H.

doi:10.1016/0272-0590(88)90247-3

Cited by 491 publications

(141 citation statements)

References 41 publications

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“…administration, and it is widely used to assess host resistance to nonimmunogenic or minimally immunogenic tumors in mice. NK cells and possibly Tc are involved in resistance to this tumor (7,27). Mice were challenged by i.v.…”

Section: Immunological and Host Resistance Assessmentsmentioning

confidence: 99%

“…This represents a fundamental gap in our understanding of the immune system, and it has important practical implications. For example, regulatory agencies (e.g., Environmental Protection Agency and Food and Drug Administration) evaluate environmental chemicals and drugs for potential adverse effects on immunocompetence, typically by using a panel of functional assays (7). Such agents seldom affect a single immunological parameter (8), and there is no effective way at present to predict the impact on host resistance of small to moderate changes in multiple immunological parameters.…”

mentioning

confidence: 99%

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Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Keil¹,

Luebke

Pruett

2001

The Journal of Immunology

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Although reductionist experimental designs are excellent for identifying cells, molecules, or functions involved in resistance to particular microbes or cancer cells, they do not provide an integrated, quantitative view of immune function. In the present study, mice were treated with either dexamethasone (DEX) or cyclosporin A (CyA), and immune function and host resistance were evaluated. Multivariate statistical methods were used to describe the relative importance of a broad range of immunological parameters for host resistance in mice treated with various dosages of DEX. Multiple regression and logistic regression analysis indicated that changes in 24 immunological parameters explained a substantial portion of the changes in resistance to B16F10 tumor cells or streptococcus group B. However, at least 40% of the change in host resistance remained unexplained. DEX at all dosages substantially suppressed numerous relevant immunological parameters, but significantly decreased resistance to Listeria monocytogenes only at the highest dosage. In contrast, CyA substantially decreased resistance to L. monocytogenes at dosages that caused relatively minor suppression of just a few immunological parameters (unfortunately, CyA data and host resistance data for L. monocytogenes were not suitable for multivariate analysis). These results illustrate that mathematical models can be used to explain changes in host resistance on the basis of changes in immune parameters, and that moderate changes in relevant immunological parameters may not produce the types of changes in host resistance expected on the basis of results from reductionist experimental designs.

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Section: Immunological and Host Resistance Assessmentsmentioning

confidence: 99%

mentioning

confidence: 99%

Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Keil¹,

Luebke

Pruett

2001

The Journal of Immunology

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“…In addition to the endpoint evaluated, multiple T-dependent antigens are available and utilized in immunotoxico-logical evaluations. Among those most often used include SRBC, keyhole limpet hemocyanin (KLH), chicken gamma globulin and tetanus toxiod (Luster et al, 1988;Temple et al, 1993;Smith et al, 2003;Gore et al, 2004). Even when the same T-dependent antigen, e.g., KLH, is utilized, the amount used to sensitize the rodent for evaluation of the primary antibody response can have marked differences on the results obtained (Peachee et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Comparison of Primary Immune Responses to SRBC and KLH in Rodents

White

Sheth

Peachee

2007

Journal of Immunotoxicology

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In rodents, the Plaque Assay, T-dependent antibody response to sheep erythrocytes (SRBC), has been reported to be a sensitive and predictive functional immune assay for detecting immunomodulatory compounds. However, various laboratories have chosen to use ELISA-based assays for evaluating the primary immune response in rodents. The ELISA-based assays offer several advantages over the Plaque Assay, which make them attractive for use in immunotoxicological evaluations. Among the most popular antigens used in the ELISA-based assays are SRBC and more recently KLH. While the Plaque Assay and the ELISA-based assays are both capable of evaluating the humoral immune response, they are measuring different endpoints. The Plaque Assay focuses primarily on splenic effects. ELISA-based assays, which use serum from immunized animals, are holistic in nature in that these assays measure effects of antibody production on the spleen, lymph nodes, and bone marrow. Depending on the drug or compound evaluated, different effects and degrees of sensitivity can be seen with the Plaque Assay and ELISA-based assays. One recent finding is that the sensitizing dose of KLH used in the KLH ELISA differentially affects the responses observed in rodents. Even within the same species, different strains of mice and rats produce different magnitudes of responses to the same sensitizing dose. A key component of this discussion focuses on the sensitivity of the Plaque Assay as compared to KLH ELISA-based assays. These assays were evaluated by comparing the response obtained following administration of several known immunosuppressive agents, including cyclophosphamide, azathioprine, cyclosporine A and dexamethasone. The effects on the primary IgM immune response in the B 6 C 3 F 1 mice, the primary immunotoxicological rodents used by National Toxicology Program, and in the Sprague-Dawley rat, the primary rodent models used by industry are addressed.

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“…Various organizations (Organization for Economic Cooperation and Development, OECD, U.S. National Toxicology Program, NTP, Dutch National Institute of Public and the Environment, RIVM, US Food and Drug Administration, FDA, U.S. Environmental Protection Agency, EPA) that conduct testing for immunotoxicity have proposed different approaches to immunotoxicity testing that include validated immune testing protocols for both animals, as reviewed by Luster et al [1988] and Van Loveren and Vos [1989], and humans, as reviewed by Tryphonas, 2001. OECD have proposed guidelines for testing the toxicity of chemicals (guideline number 407) that were adopted in many countries.…”

Section: Immunotoxicity Testingmentioning

confidence: 99%

“…There is not always general agreement, however, as to which tests fall into which levels. In any case, it is agreed that the most effective approach to immunotoxicity testing is to perform a battery of tests, and interpret them in their entirety, not on the analysis of a single parameter [Dean, 1979;Vos, 1980;Luster et al, 1988].…”

Section: Immunotoxicity Testingmentioning

confidence: 99%

Immunotoxic effects of chemicals: A matrix for occupational and environmental epidemiological studies

Veraldi¹,

Costantini²,

Bolejack³

et al. 2006

American J Industrial Med

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Background Many biological and chemical agents have the capacity to alter the way the immune system functions in human and animals. This study evaluates the immunotoxicity of 20 substances used widely in work environments. Methods A systematic literature search on the immunotoxicity of 20 chemicals was performed. The first step was to review literature on immunotoxicity testing and testing schemes adopted for establishing immunotoxicity in humans. The second step consisted of providing a documentation on immunotoxicity of substances that are widely used in work environment, by building tables for each chemical of interest (benzene, trichloroethylene, PAHs, crystalline silica, diesel exhausts, welding fumes, asbestos, styrene, formaldehyde, toluene, vinyl chloride monomer, tetrachloroethylene, chlorophenols, 1,3‐butadiene, mineral oils, P‐dichlorobenzene, dichloromethane, xylene, 1,1,1‐trichloroethane, ethylene oxide). The third step was the classification of substances; an index (strong, intermediate, weak, nil) was assigned on the basis of the evidence of toxicity and type of immunotoxic effects (immunosuppression, autoimmunity, hypersensitivity) on the basis of the immune responses. Finally substances were assigned a score of immunotoxic power. Results Tables have been produced that include information for the 20 substances of interest, based on 227 animal studies and 94 human studies. Each substance was assigned an index of immunotoxic evidence, a score of immunotoxic power and type of immunotoxic effect. Conclusions This matrix can represent a tool to identify chemicals with similar properties concerning the toxicity for the immune system, and to interpret epidemiological studies on immune‐related diseases. Am. J. Ind. Med. 2006. © 2006 Wiley‐Liss, Inc.

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Development of a testing battery to assess chemical-induced immunotoxicity: National toxicology program's guidelines for immunotoxicity evaluation in mice

Cited by 491 publications

References 41 publications

Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Comparison of Primary Immune Responses to SRBC and KLH in Rodents

Immunotoxic effects of chemicals: A matrix for occupational and environmental epidemiological studies

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