Lessons learned, challenges, and opportunities: the U.S. Endocrine Disruptor Screening Program.

In 1996, the U.S. Congress passed the Food Quality Protection Act and amended the Safe Drinking Water Act (SDWA) requiring the U.

The new revolution in toxicology: the good, the bad, and the ugly.

In 2007, the United States National Academy of Sciences issued a report entitled Toxicity Testing in the 21(st) Century: A Vision and a Strategy. The report reviewed the state of the science and outlined a strategy for the future of toxicity testing. One of the more significant components of the vision established by the report was an emphasis on toxicity testing in human rather than animal systems.

Juvenile immunotoxicology.

Developmental immunotoxicity (DIT) testing is centered around the concern that exposure to immunotoxicants early in development may result in enhanced susceptibility of, or unique or more persistent effects on, the immune system, in comparison to adult exposure. Developmental immunotoxicity has been the focus of numerous workshops and reviews for at least fifteen years. Most of these earlier activities have focused on both environmental chemicals and pharmaceuticals and have concluded that the best approach to DIT is to address the possible impacts of exposure during all of the critical windows of development.

Accelerating the development of 21st-century toxicology: outcome of a Human Toxicology Project Consortium workshop.

The U.S. National Research Council (NRC) report on "Toxicity Testing in the 21st century" calls for a fundamental shift in the way that chemicals are tested for human health effects and evaluated in risk assessments.

Human and environmental health challenges for the next decade (2010–2020).

The public health and environmental communities will face many challenges during the next decade. To identify significant issues that might be addressed as part of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) scientific portfolio, an expert group of key government, academic, and industry scientists from around the world were assembled in 2009 to map the current and future landscape of scientific and regulatory challenges. The value of the scientific mapping exercise was the development of a tool which HESI, individual companies, research institutions, government agencies, and regulatory authorities can use to anticipate key challenges, place them into context, and thus strategically refine and expand scientific project portfolios into the future.

Interlaboratory study of the primary antibody response to sheep red blood cells in outbred rodents following exposure to cyclophosphamide or dexamethasone.

EPA guidelines provide a choice in evaluating humoral immune system function in rats and mice immunized with sheep red blood cells (sRBC): an antibody-forming cell (AFC) assay or a sRBC-specific serum IgM enzyme-linked immunosorbent assay (ELISA). Four different laboratories used both methods to detect suppression of the antibody response by cyclophosphamide (CP) or dexamethasone (DEX). Attempts were made to minimize interlaboratory variability through the use of common reagents and vendors; each laboratory used the same source for rodents, immunosuppressive agents, and one sheep for sRBCs, and determined optimal sRBC concentration for immunization and peak day of antibody response in female CD rats and CD1 mice.

TCDD-mediated suppression of the in vitro anti-sheep erythrocyte IgM antibody forming cell response is reversed by interferon-gamma.

Suppression of humoral immune responses by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been well established to require the aryl hydrocarbon receptor; however, the downstream mechanisms for this immunotoxic response remain poorly understood. Based on evidence demonstrating that primary hepatocytes pretreated with interferon-gamma (IFN-gamma) exhibited decreased induction of cytochrome P450 1A1 (CYP1A1) by TCDD, and that serum factors alter the sensitivity of the in vitro T-cell-dependent IgM antibody forming cell (AFC) response, it was hypothesized that IFN-gamma attenuates suppression of humoral immune responses by TCDD. In fact, concomitant addition of IFN-gamma (100 U/ml) produced a concentration-related attenuation of TCDD-mediated suppression of the anti-sheep erythrocyte (anti-sRBC) IgM AFC response.

Predicting future human and environmental health challenges: the Health and Environmental Sciences Institute's scientific mapping exercise.

To predict important strategic issues in product safety during the next 10 years, the Health and Environmental Sciences Institute (HESI) of the International Life Sciences Institute initiated a mapping exercise to evaluate which issues are likely to be of societal, scientific, and regulatory importance to regulatory authorities, the HESI membership, and the scientific community at large. Scientists representing government, academia, and industry participated in the exercise. Societal issues identified include sensitive populations, alternative therapies, public education on the precautionary principle, obesity, and aging world populations.

Dose response considerations in risk assessment--an overview of recent ILSI activities.

This paper will provide some perspective on the role that a consideration of the dose-response has played (past), is playing (present) and will play (future) in human risk assessment with special emphasis on a number of recent activities undertaken by various components of the International Life Sciences Institute (ILSI). The dose-response is a critically important concept in every aspect of biomedical science, including toxicology. A characterization of the dose response has been recognized as one of the four essential components of risk assessment since the release of the NRC/NAS report in 1983, and understanding the dose-response curve is the basis for regulatory toxicology.

What's so special about the developing immune system?

The evolution of the subdiscipline of developmental immunotoxicology (DIT) as it exists today has been shaped by significant regulatory pressures as well as key scientific advances. This review considers the role played by legislation to protect children's health, and on the emergence of immunotoxcity and developmental immunotoxicity guidelines, as well as providing some context to the need for special attention on DIT by considering the evidence that the developing immune system may have unique susceptibilities when compared to the adult immune system. Understanding the full extent of this potential has been complicated by a paucity of data detailing the development of the immune system during critical life stages as well as by the complexities of comparisons across species.

Relevance and follow-up of positive results in in vitro genetic toxicity assays: an ILSI-HESI initiative.

In vitro genotoxicity assays are often used to screen and predict whether chemicals might represent mutagenic and carcinogenic risks for humans. Recent discussions have focused on the high rate of positive results in in vitro tests, especially in those assays performed in mammalian cells that are not confirmed in vivo. Currently, there is no general consensus in the scientific community on the interpretation of the significance of positive results from the in vitro genotoxicity assays.

Evaluating emerging issues in epidemiology.

Industry and government institutions need a credible approach for evaluating and responding to emerging public health issues. Representatives of industry, government, and academia met under the auspices of the International Life Sciences Institute's Health and Environmental Sciences Institute (HESI) to develop successful strategies for dealing with emerging issues based on historical case studies. The case studies chosen for evaluation were (1) tampon use and toxic shock syndrome; (2) hazardous waste and childhood cancer risk in Toms River, New Jersey; (3) fenfluramine and phentermine use and valvular heart disease; (4) silicone breast implants and cancer and auto-immune disease; and (5) progestational drugs and birth defects.

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.

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.

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.

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.

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.

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.

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.

A proposed testing framework for developmental immunotoxicology (DIT).

A group of thirty immunotoxicology experts from the U.S. and E.

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.

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.