Search PubMed⌕ Search

Biomedical subjects

Michael P Holsapple

Publications and source records attributed to Michael P Holsapple.

14 recordsLinked to original sources
PubMed2007

Methodologies for developmental immunotoxicity (DIT) testing.

Developmental immunotoxicity has gained increasing recognition as a significant factor influencing the risk of later life disease. Based on the data collected thus far on different chemicals and drugs, the developing immune system can be significantly more sensitive than the adult immune system to xenobiotic-induced insult. There are distinct differences between the immune system surrounding birth and that in the mature adult as well as differences in the nature of immunotoxic changes based on age. Immunosuppresssion is not the only concern. Immunotoxic changes that increase the risk for allergic or autoimmune responses should also be considered. Therefore, one should not assume that immunotoxicity assays validated for adult exposure assessment are inherently the most predictive for developmental immunotoxicology (DIT) evaluation. Many of those adult-based protocols were developed solely to detect immunosuppression, whereas DIT concerns include shifts in immune balance. For this reason, it is useful to examine the various immune endpoints that have been employed in recent perinatal immunotoxicity studies, compare those against routine adult immunotoxicity evaluation protocols, and consider the options that are available for effective DIT testing. The results published on several chemicals and drugs in recent years suggest that functional tests are a front-line priority for perinatal immunotoxicity detection and that a combination of at least two functional tests (such as a multi-isotype T-dependent antibody response (TDARs), and a cell-mediated immune response assay such as the delayed-type hypersensitivity assay and/or T cell or NK cytotoxicity assays) should be paired with immune cell populations and histopathological analysis. Cytokine production measurements offer outstanding promise and may eventually be able to be substituted for other more laborious procedures. However, multi-cytokine analysis needs to be standardized in terms of optimum source for analysis and protocol.

Animals↗
PubMed2006

Immunotoxicogenomics: the potential of genomics technology in the immunotoxicity risk assessment process.

Evaluation of xenobiotic-induced changes in gene expression as a method to identify and classify potential toxicants is being pursued by industry and regulatory agencies worldwide. A workshop was held at the Research Triangle Park campus of the Environmental Protection Agency to discuss the current state-of-the-science of "immunotoxicogenomics" and to explore the potential role of genomics techniques for immunotoxicity testing. The genesis of the workshop was the current lack of widely accepted triggering criteria for Tier 1 immunotoxicity testing in the context of routine toxicity testing data, the realization that traditional screening methods would require an inordinate number of animals and are inadequate to handle the number of chemicals that may need to be screened (e.g., high production volume compounds) and the absence of an organized effort to address the state-of-the-science of toxicogenomics in the identification of immunotoxic compounds. The major focus of the meeting was on the theoretical and practical utility of genomics techniques to (1) replace or supplement current immunotoxicity screening procedures, (2) provide insight into potential modes or mechanisms of action, and (3) provide data suitable for immunotoxicity hazard identification or risk assessment. The latter goal is of considerable interest to a variety of stakeholders as a means to reduce animal use and to decrease the cost of conducting and interpreting standard toxicity tests. A number of data gaps were identified that included a lack of dose response and kinetic data for known immunotoxic compounds and a general lack of data correlating genomic alterations to functional changes observed in vivo. Participants concluded that a genomics approach to screen chemicals for immunotoxic potential or to generate data useful to risk assessors holds promise but that routine use of these methods is years in the future. However, recent progress in molecular immunology has made mode and mechanism of action studies much more practical. Furthermore, a variety of published immunotoxicity studies suggest that microarray analysis is already a practical means to explore pathway-level changes that lead to altered immune function. To help move the science of immunotoxicogenomics forward, a partnership of industry, academia, and government was suggested to address data gaps, validation, quality assurance, and protocol development.

Animals↗
PubMed2005

Assessing the potential to induce respiratory hypersensitivity.

Acute and repeat dose inhalation studies have been an important part of the safety assessment of drugs, chemicals, and other products throughout the world for many years. It is known that damage to the respiratory tract can be triggered either by nonspecific irritation or by specific immune-mediated pathogenesis, and it is acknowledged that traditional inhalation studies are not designed to address fully the impact of the latter. It is also recognized that different types of immune-mediated responses can be triggered by different classes of compounds and that some immune reactions in the lung are life threatening. As such, it is important to understand as fully as possible the basis for the immune-mediated damage to the lung in order to characterize adequately the risks of individual chemicals or proteins. It is against this background that a review of the methods used to assess the potential for immune-mediated respiratory hypersensitivity was conducted. The primary objectives of this review are to discuss appropriate methods for identifying and characterizing respiratory hypersensitivity hazards and risks; and to identify key data gaps and related research needs with respect to respiratory hypersensitivity testing. The following working definition of respiratory hypersensitivity was formulated: a hypersensitivity response in the respiratory tract precipitated by a specific immune response, mediated by multiple mechanisms, including IgE antibody. Because of the importance played by various classes of compounds, the subsequent sections of this review will consider protein-specific, chemical-specific, and drug-specific aspects of respiratory hypersensitivity.

Drug Hypersensitivity↗
PubMed2005

Mode of action in relevance of rodent liver tumors to human cancer risk.

Hazard identification and risk assessment paradigms depend on the presumption of the similarity of rodents to humans, yet species specific responses, and the extrapolation of high-dose effects to low-dose exposures can affect the estimation of human risk from rodent data. As a consequence, a human relevance framework concept was developed by the International Programme on Chemical Safety (IPCS) and International Life Sciences Institute (ILSI) Risk Science Institute (RSI) with the central tenet being the identification of a mode of action (MOA). To perform a MOA analysis, the key biochemical, cellular, and molecular events need to first be established, and the temporal and dose-dependent concordance of each of the key events in the MOA can then be determined. The key events can be used to bridge species and dose for a given MOA. The next step in the MOA analysis is the assessment of biological plausibility for determining the relevance of the specified MOA in an animal model for human cancer risk based on kinetic and dynamic parameters. Using the framework approach, a MOA in animals could not be defined for metal overload. The MOA for phenobarbital (PB)-like P450 inducers was determined to be unlikely in humans after kinetic and dynamic factors were considered. In contrast, after these factors were considered with reference to estrogen, the conclusion was drawn that estrogen-induced tumors were plausible in humans. Finally, it was concluded that the induction of rodent liver tumors by porphyrogenic compounds followed a cytotoxic MOA, and that liver tumors formed as a result of sustained cytotoxicity and regenerative proliferation are considered relevant for evaluating human cancer risk if appropriate metabolism occurs in the animal models and in humans.

Animals↗
PubMed2005

Research strategies for safety evaluation of nanomaterials, part II: toxicological and safety evaluation of nanomaterials, current challenges and data needs.

This article summarizes a roundtable discussion held at the 2005 Society of Toxicology Annual Meeting in New Orleans, LA. The purpose of the roundtable was to review the current challenges and data needs for conducting toxicological and safety evaluations for nanomaterials, with the goals of presenting the current state-of-the science on the safety of nanomaterials and bringing together scientists representing government, academia, and industry to identify priorities for developing data to facilitate risk assessments for these materials. In this summary, the unique physicochemical properties associated with nanomaterials are reviewed in the context of the difficulties associated with measuring and characterizing them. In addition, the development of appropriate hazard data, the collection of accurate human and environmental exposure information, and the development of a better fundamental understanding of the modes of action for nanomaterials are discussed as factors that will impact the development of comprehensive toxicological and safety evaluations.

Animals↗
PubMed2005

Developmental toxicology evaluations--issues with including neurotoxicology and immunotoxicology assessments in reproductive toxicology studies.

Developmental and reproductive toxicology (DART) has routinely been a part of safety assessment. Attention is now focused on the effects of chemicals on the developing nervous and immune systems. This focus on developmental neurotoxicology (DNT) and developmental immunotoxicology (DIT) is based on the premise that children differ from adults in some aspects of their biology and, thus, may also differ in their responses to chemicals. This session's objective was to discuss issues common to DNT and DIT as they relate to DART protocols, including high dose selection and maternal toxicity, adequacy of pup exposure during lactation, use of a different dosing paradigm for DART versus DNT or DIT studies, and whether DIT and DNT endpoints can be incorporated into a single DART study for hazard identification purposes. Consensus was achieved on all topics except the adequacy for risk assessment purposes of the use of a limited number of endpoints for DIT and DNT, with the DNT endpoints being the primary focus of disagreement. Panelists indicated that a combination study design for hazard identification was feasible, though flexibility to meet the scientific needs of the project was emphasized. The adequacy of existing triggers for additional developmental studies was also questioned. Panelists iterated the importance of understanding pup exposure during the various life stages and the use of toxicokinetic data in designing these studies. The group agreed to consider the HESI ACSA Life Stages Task Force recommendations as a next step to address some of the issues and challenges raised during this session.

Abnormalities, Drug-Induced↗
PubMed2004

A proposed testing framework for developmental immunotoxicology (DIT).

A group of thirty immunotoxicology experts from the U.S. and E.U. representing government, industry, and academia met in May 2003, in Washington, D.C., to reach consensus regarding the most appropriate methods to assess developmental immunotoxicology (DIT) for hazard identification, including under what conditions such testing might be required. The following points represent the major conclusions from this roundtable discussion: (1) the rat is the preferred model; (2) any DIT protocol should be based on immune assays already validated; (3) DIT methods should be incorporated into standard developmental and reproductive toxicity protocols to the extent possible rather than a "stand-alone" protocol; (4) the approach to address DIT potential should be similar for chemicals and drugs, but the experimental design should be flexible and should reflect the specific questions to be answered; (5) it is possible to utilize a study design that assesses all critical windows in one protocol, with the results leading to further study of specific effects, as warranted; (6) animals should be exposed throughout the treatment protocol; (7) the triggers for DIT may include structure-activity-relationships, results from other toxicity studies, the intended use of a drug/chemical and/or its anticipated exposure of neonates and/or juveniles.

Animals↗
PubMed2004

Symposium summary: children's health risk--what's so special about the developing immune system?

In recent years, there has been increasing regulatory pressure to protect the health of children, with the basic tenet being that children differ significantly from adults in their biological or physiological responses to chemical exposures. In a regulatory context, this has been translated to mean a requirement for an additional 10-fold safety factor for environmental contaminants, specialized tests, or both. Much of the initial focus has been on the developing endocrine and nervous systems; but increasingly, the developing immune system has been identified as a potential target organ for chemically mediated toxicity. More recently, the question has been raised regarding whether the current state of science supports the creation of developmental immunotoxicology (DIT) test guidelines. What is needed is a risk-based evaluation of the biology associated with the proposed differential sensitivity between children and adults and the impact of that assessment on additional regulatory measures to protect children in risk assessment analyses. Additionally, an understanding of whether the developing immune system shows greater susceptibility, either qualitatively or quantitatively, to chemical perturbation is critical. To address the question "What's so special about the developing immune system?" a symposium was organized for the 2003 Society of Toxicology annual meeting that brought together risk assessors, clinicians, immunologists, and toxicologists.

Adolescent↗
PubMed2004

Skf 525-A induces cocaine N-demethylase, ethoxyresorufin O-deethylase, and pentoxyresorufin O-dealkylase activities by induction of cytochrome p-450 2B in female B6C3F1 mice.

Studies demonstrated that cocaine-induced immunosuppression is mediated by metabolites of cocaine. Although SKF 525-A inhibited cocaine N-demethylation in liver S9 fractions isolated from female B6C3F1 mice, our study showed that pretreatment of mice with SKF 525-A potentiated cocaine-induced suppression of the antibody response to sheep red blood cells. An increase in formaldehyde generation was subsequently shown following incubation of cocaine with the S9 fractions prepared from SKF 525-A-treated mice, indicating the possibility of cytochrome P-450 (CYP) induction. Therefore, the inductive effects of SKF 525-A on CYP enzyme activities and proteins were investigated in female B6C3F1 mice to elucidate the potentiation of cocaine-induced immunosuppression by SKF 525-A. When SKF 525-A was administered at 10, 20, or 40 mg/kg/d intraperitoneally for 7 consecutive days, both ethoxyresorufin O-deethylase and pentoxyresorufin O-dealkylase activities were induced dose-dependently. Furthermore, the induction of enzymatic activity was time dependent. Meanwhile, when the type of isozyme induced by SKF 525-A was analyzed by Western immunoblotting with monospecific anti-CYP 1A and anti-CYP 2B antibodies, only the CYP 2B appeared to be induced. From in vitro inhibition studies with monoclonal antibodies, it was confirmed that the induced activity of ethoxyresorufin O-deethylase by SKF 525-A was due to increased levels of CYP 2B proteins. Our present results provide an explanation for the potentiation of cocaine-induced immunosuppression by repeated exposure to SKF 525-A. Our results also indicate that ethoxyresorufin O-deethylase, a selective substrate for CYP 1A, may also be catalyzed by CYP 2B.

Animals↗
PubMed2003

Workshop overview: approaches to the assessment of the allergenic potential of food from genetically modified crops.

There is a need to assess the safety of foods deriving from genetically modified (GM) crops, including the allergenic potential of novel gene products. Presently, there is no single in vitro or in vivo model that has been validated for the identification or characterization of potential food allergens. Instead, the evaluation focuses on risk factors such as source of the gene (i.e., allergenic vs. nonallergenic sources), physicochemical and genetic comparisons to known allergens, and exposure assessments. The purpose of this workshop was to gather together researchers working on various strategies for assessing protein allergenicity: (1) to describe the current state of knowledge and progress that has been made in the development and evaluation of appropriate testing strategies and (2) to identify critical issues that must now be addressed. This overview begins with a consideration of the current issues involved in assessing the allergenicity of GM foods. The second section presents information on in vitro models of digestibility, bioinformatics, and risk assessment in the context of clinical prevention and management of food allergy. Data on rodent models are presented in the next two sections. Finally, nonrodent models for assessing protein allergenicity are discussed. Collectively, these studies indicate that significant progress has been made in developing testing strategies. However, further efforts are needed to evaluate and validate the sensitivity, specificity, and reproducibility of many of these assays for determining the allergenicity potential of GM foods.

Animals↗
PubMed2003

Developmental immunotoxicity testing: a review.

There are currently no validated or widely accepted methods for evaluating the effects of a chemical on the developing immune system. Nonetheless because of concerns over children's health issues, specifically the possibility that the very young are uniquely susceptible to chemical perturbation, governmental regulators are beginning to ask for information about potential effects on the developing immune system. This paper will address the following three goals. First, an update of the regulatory pressures for developmental immunotoxicology will be presented from a U.S. perspective. Second, an update on the state of the science of developmental immunotoxicology will be presented with an emphasis on results from a recent collaboration between Dow, DuPont and Cornell University. Finally, the principle conclusions from a recent ILSI/HESI workshop will be summarized. At this workshop, it was generally acknowledged that there are a variety of techniques available for assessing immunosuppression in adult animal models. However, it was emphasized that there is uncertainty about how to apply these approaches to a developing animal, especially if the goal is to have some standard procedure(s) that could be applied for regulatory risk assessment. Ultimately, the primary conclusion from this workshop was that developmental immunotoxicology, as a science, is still in its infancy and is not ready to be applied in a risk assessment strategy.

Animals↗
PubMed2003

Species comparison of anatomical and functional immune system development.

The components of the immune system have not been traditionally emphasized as potential target organs in standard developmental and reproductive toxicity (DART) protocols. A number of workshops have been organized in recent years to examine scientific questions that underlie developmental immunotoxicity tests, and the interpretation of results as they relate to human risk assessment. A key question that must be addressed is to determine the most appropriate species and strains to model the developing human immune system. The objective of this review is to compare the anatomical and functional development of the immune system in several species important to either preclinical studies for drug development or safety assessments for chemicals, with what is known in humans. The development of the immune system in humans will be compared to what is known in mice, rats, dogs and nonhuman primates.

Age Distribution↗
PubMed2002

Autoimmunity by pesticides: a critical review of the state of the science.

The goals of this paper will be to present a critical review of the state of the science of pesticides and autoimmunity, and to discuss research that addresses the potential links between environmental chemicals and autoimmune disease. To date, the science of immunotoxicology has primarily focused on immunosuppression and hypersensitivity/allergy, and test methods are available to address these outcomes. So much progress has been made to address immunosuppression and contact sensitization that there are regulatory guidelines in the U.S. included in the registration of pesticides. In contrast, there are no validated approaches to assess autoimmunity. The overall objective of this paper will be to use pesticides as an important class of environmental chemicals to critically evaluate the state of the science for addressing chemical-induced autoimmunity. Specific examples of studies with pesticides will be discussed in the context of the following types of approaches: animal studies using standard immunotoxicological parameters; animal studies using specialized models of autoimmunity; human studies after environmental or occupational exposure; and human studies after accidental poisoning.

Animals↗