Host Resistance Assays.

The goal of immunotoxicity testing is to obtain data useful for immunotoxicity safety assessment. Guidance in the performance of immunotoxicity safety evaluations is provided in documents from the US EPA for chemicals and the ICH S8 document for pharmaceuticals. The ICH S8 document outlines a tiered approach that includes (1) standard toxicity studies with associated hematology, immune system organ weights, and histopathology data; (2) functional assays, such as cytotoxic T lymphocyte (CTL) assays, natural killer (NK) cell assays, respiratory burst, phagocytosis, and T-cell-dependent antibody response (TDAR) assays; and (3) host resistance assays.

Effects of Simulated Smog Atmospheres in Rodent Models of Metabolic and Immunologic Dysfunction.

Air pollution is a diverse and dynamic mixture of gaseous and particulate matter, limiting our understanding of associated adverse health outcomes. The biological effects of two simulated smog atmospheres (SA) with different compositions but similar air quality health indexes were compared in a nonobese diabetic rat model (Goto-Kakizaki, GK) and three mouse immune models (house dust mite (HDM) allergy, antibody response to heat-killed pneumococcus, and resistance to influenza A infection). In GK rats, both SA-PM (high particulate matter) and SA-O (high ozone) decreased cholesterol levels immediately after a 4-h exposure, whereas only SA-O increased airflow limitation.

Associating Changes in the Immune System with Clinical Diseases for Interpretation in Risk Assessment.

This overview is an update of the unit originally published in 2004. While the basic tenets of immunotoxicity have not changed in the past 10 years, several publications have explored the application of immunotoxicological data to the risk assessment process. Therefore, the goal of this unit is still to highlight relationships between xenobiotic-induced immunosuppression and risk of clinical diseases progression.

Toxicological assessments of rats exposed prenatally to inhaled vapors of gasoline and gasoline-ethanol blends.

The primary alternative to petroleum-based fuels is ethanol, which may be blended with gasoline in the United States at concentrations up to 15% for most automobiles. Efforts to increase the amount of ethanol in gasoline have prompted concerns about the potential toxicity of inhaled ethanol vapors from these fuels. The well-known sensitivity of the developing nervous and immune systems to ingested ethanol and the lack of information about the neurodevelopmental toxicity of ethanol-blended fuels prompted the present work.

Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARα and T- and B-cell targeting.

T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARα)-dependent and if suppression is associated with specific targeting of T- or B-cells, three separate experiments were conducted: (1) female PPARα constitutive knockout (PPARα KO; B6.

Toxicological outcomes in rats exposed to inhaled ethanol during gestation.

Recent legislation has encouraged replacing petroleum-based fuels with renewable alternatives including ethanol, which is typically blended with gasoline in the United States at concentrations up to 10%, with allowances for concentrations up to 85% for some vehicles. Efforts to increase the amount of ethanol in gasoline have prompted concerns about the potential toxicity of inhaled ethanol vapors from these fuels. The well-known sensitivity of the developing nervous and immune systems to ingested ethanol, and the lack of information about its toxicity by inhalation prompted the present work on its potential developmental effects in a rat model.

Perfluorinated compounds: emerging POPs with potential immunotoxicity.

Perfluorinated compounds (PFCs) have been recognized as an important class of environmental contaminants commonly detected in blood samples of both wildlife and humans. These compounds have been in use for more than 60 years as surface treatment chemicals, polymerization aids, and surfactants. They possess a strong carbon-fluorine bond, which leads to their environmental persistence.

Comprehensive assessment of a chlorinated drinking water concentrate in a rat multigenerational reproductive toxicity study.

Some epidemiological studies report associations between drinking water disinfection byproducts (DBPs) and adverse reproductive/developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects.

Evaluation of anti-nuclear antibodies and kidney pathology in Lewis rats following exposure to Libby amphibole asbestos.

The prevalence of anti-nuclear antibodies (ANA) and self-reported systemic autoimmune diseases were increased in residents of Libby, MT, as was the incidence of ANA in Lewis rats exposed to Libby amphibole (LA) asbestos. However, rats induced to develop rheumatoid arthritis (RA) did not develop autoantibodies associated with RA, nor was RA exacerbated by LA exposure, suggesting that increased ANA expression might be related to some other autoimmune process. Libby residents self-reported increased numbers of physician-diagnosed cases of systemic lupus erythematosus (SLE).

Immunotoxicology: fifty years of global scientific progress.

The Immunotoxicology Specialty Section of the Society of Toxicology (SOT) celebrated the 50(th) Anniversary of the SOT by constructing a poster to highlight the milestones of Immunotoxicology during that half-century period. This poster was assembled by an ad hoc committee and intertwines in words, citations, graphics, and photographs our attempts to capture a timeline reference of the development and progressive movement of immunotoxicology across the globe. This poster was displayed during the 50(th) Annual SOT Meeting in Washington DC in March, 2011.

Immunotoxicology and its application in risk assessment.

Immunotoxicology is the study of undesired modulation of the immune system by extrinsic factors. Toxicological assessments have demonstrated that the immune system is a target following exposure to a diverse group of xenobiotics including ultraviolet radiation, chemical pollutants, therapeutics, and recreational drugs. There is a well-established cause and effect relationship between suppression of the immune response and reduced resistance to infections and certain types of neoplasia.

Effects of Libby amphibole asbestos exposure on two models of arthritis in the Lewis rat.

Epidemiological data suggest that occupational exposure to the amphibole-containing vermiculite in Libby, MT, was associated with increased risk for developing autoimmune diseases and had an odds ratio of 3.23 for developing rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) and the peptidoglycan-polysaccharide (PG-PS) models of RA were employed to determine whether exposure to Libby amphibole (LA) induced a more rapid onset, increased expression, or prolonged course of RA.

Immunotoxicant screening and prioritization in the twenty-first century.

Current immunotoxicity testing guidance for drugs, high production-volume chemicals, and pesticides specifies the use of animal models to assess potential biomarkers of immune system effects (e.g., lymphoid organ and bone marrow indices, histopathology) or actual measures of immune function (e.

Immunotoxicological profile of chloramine in female B6C3F1 mice when administered in the drinking water for 28 days.

Monochloramine has been used to provide a disinfecting residual in water distribution systems where it is difficult to maintain an adequate free-chlorine residual or where disinfection by-product formation is of concern. The goal of this study was to characterize the immunotoxic effects of chloramine in female B(6)C(3)F(1) mice when administered via the drinking water. Mice were exposed to chloramine-containing deionized tap water at 2, 10, 20, 100, or 200 ppm for 28 days.

Effect of maternal exposure to ozone on reproductive outcome and immune, inflammatory, and allergic responses in the offspring.

There is growing concern that exposure to air pollutants during pregnancy affects health outcomes in the offspring due to alterations in the development of immune and other homeostatic processes. To assess the risks of maternal inhalation exposure to ozone (O(3)), timed pregnant BALB/c mice were exposed to different concentrations of O(3) (0, 0.4, 0.

Immunotoxicity of dibromoacetic acid administered via drinking water to female B₆C₃F₁ mice.

Dibromoacetic acid (DBA) is a disinfection by-product commonly found in drinking water as a result of chlorination/ ozonation processes. The Environmental Protection Agency estimates that more than 200 million people consume disinfected water in the United States. This study was conducted to evaluate the potential immunotoxicological effects of DBA exposure when administered for 28 days via drinking water to B₆C₃F₁ mice, at concentrations of 125, 500, and 1000 mg/L.

Effects of prenatal diesel exhaust inhalation on pulmonary inflammation and development of specific immune responses.

There is increasing evidence that exposure to air pollutants during pregnancy can result in a number of deleterious effects including low birth weight and the incidence of allergic asthma. To investigate the in utero effects of DE exposure, timed pregnant BALB/c mice were exposed to 0, 0.8 or 3.

Parasite challenge as host resistance models for immunotoxicity testing.

Identification of potentially immunosuppressive compounds typically involves assessing a combination of observational endpoints as surrogates for functional endpoints and functional endpoints as surrogates for resistance to infectious or neoplastic disease. Host resistance assays are considered to be the "gold standard" against which suppression of immune function at the molecular or cellular level can be judged, because resistance to infection, regardless of the actual pathogen, involves multiple pathways of effector function to neutralize or eliminate pathogens. Resistance to infection with the parasitic nematode Trichinella spiralis has been used to assess immune function following exposure to a variety of immunotoxicants at the whole animal level.

Approaches for assessing risks to sensitive populations: lessons learned from evaluating risks in the pediatric population.

Assessing the risk profiles of potentially sensitive populations requires a "tool chest" of methodological approaches to adequately characterize and evaluate these populations. At present, there is an extensive body of literature on methodologies that apply to the evaluation of the pediatric population. The Health and Environmental Sciences Institute Subcommittee on Risk Assessment of Sensitive Populations evaluated key references in the area of pediatric risk to identify a spectrum of methodological approaches.

Immunotoxicological profile of chloroform in female B6C3F1 mice when administered in drinking water.

Chloroform can be formed as a disinfection by-product during water chlorination, one of the primary modalities for purifying municipal water supplies for human consumption. The aim of this study was to characterize the immunotoxic effects of chloroform in female B6C3F1 mice when exposure occurred via the drinking water. Consistent with human exposure, female B6C3F1 mice were exposed to chloroform-containing drinking water at 2.

Suppression of humoral immunity by perfluorooctanoic acid is independent of elevated serum corticosterone concentration in mice.

The T-cell-dependent antibody response is suppressed in mice exposed to 3.75, 7.5, 15, and 30 mg PFOA (perfluorooctanoic acid)/kg body weight (bw).

Meeting report: moving upstream-evaluating adverse upstream end points for improved risk assessment and decision-making.

Background: Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an "adverse effect" in the context of hazard identification and risk assessment.

Developmental Exposure to 1.0 or 2.5 mg/kg of Dibutyltin Dichloride Does Not Impair Immune Function in Sprague-Dawley Rats.

Organotins are used commercially as pesticides, antifouling agents, and stabilizers for polyvinyl chloride (PVC) pipe. Mono-and di-substituted butyltins, used in PVC pipe production, are of concern to the United States EPA, they leach from supply pipes into drinking water and are reported multisystem toxicants. We assessed immune function in Sprague-Dawley rats after developmental dibutyltin dichloride (DBTC) exposure.