A Tiered Approach to Life Stages Testing for Agricultural Chemical Safety Assessment

Aproposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. The ACSA Life Stages Task Force proposes a tiered approach to toxicity testing that assesses a compound's potential to cause adverse effects on reproduction, and that assesses the nature and severity of effects during development and adolescence, with consideration of the sensitivity of the elderly. While incorporating many features from current guideline studies, the proposed approach includes a novel rat reproduction and developmental study with enhanced endpoints and a rabbit development study. All available data, including toxicokinetics, ADMEdata, and systemic toxicity information, are considered in the design and interpretation of studies. Compared to existing testing strategies, the proposed approach uses fewer animals, provides information on the young animal, and includes an estimation of human exposure potential for making decisions about the extent of testing required.     

Risk Assessment of Toxaphene and its Breakdown Products: Time for a Change?

Technical toxaphene (TT) was last used in commerce in about 1982. Any environmental exposure to toxaphene in this century is to environmentally degraded forms of toxaphene, termed weathered toxaphene. Several hundred chlorinated bornane congeners have been identified in technical toxaphene. The degradation of technical toxaphene to weathered toxaphene can result in various congener mixtures, but the primary mode of degradation is dechlorination. The U.S. Environmental Protection Agency (EPA) presently estimates the risk of exposure to toxaphene by relying upon rat and mouse toxicology studies performed on technical toxaphene. No adjustment is made for the dechlorination of toxaphene in the environment. The European Union (EU), however, has modeled toxaphene risks from eating fish with chlorinated bornane residues through a series of studies on toxaphene degraded by either ultraviolet light, or biodegradation in fish. The EU risk assessment relies upon rat liver studies in vivo and mouse in vitro studies on the inhibition of gap junction intercellular communication (GJIC). This article reviews the current state of knowledge of technical and weathered toxaphene toxicology. We discuss the various current methods and opportunities to advance the risk assessment of weathered toxaphene beyond the existing U.S. EPA assessment of technical toxaphene.     

Public Policy and Headache: Observations of Health Care Policy in the US Congress From a Legislative Fellow's Perspective

Many neurologists and headache specialists are befuddled by inside the Beltway wheelings and dealings as they follow health care politics. A few of us join lobbying efforts, and even fewer become strangers in a strange land.     

A direct comparison of rejection by CD8 and CD4 T cells in a transgenic model of allotransplantation

INTRODUCTION: The relative contributions of CD4+ and CD8+ T cells to transplant rejection remain unknown. The authors integrated a previous model of CD4-mediated graft rejection with a complementary model of CD8-mediated rejection to directly compare the function of graft-reactive CD4+ and CD8+ lymphocytes in vivo in a model where rejection requires transgenic T cells. These studies allow direct comparison of CD4 and CD8 T cell responses to the same antigen without the confounding effects of T cell depletion or homeostatic proliferation. MATERIALS AND METHODS: Clone 4 and TS1 mice possess MHC class I- and II-restricted CD8+ and CD4+ T cells, respectively, which express transgenic T cell receptors that recognize the influenza hemagglutinin antigen (HA). We compared the in vivo response of CFSE-labeled, HA-specific transgenic CD8+ and CD4+ T cells after adoptive transfer into syngeneic BALB/c mice grafted with HA-expressing skin. RESULTS: As in the authors' CD4+ model, HA104 skin was consistently rejected by both Clone 4 mice (n=9, MST: 14.2) and by 5 x 10(5) Clone 4 lymphocytes transferred to naive BALB/c hosts that do not otherwise reject HA+ grafts. Rejection correlated with extensive proliferation of either graft-reactive T cell subset in the draining lymph nodes, and antigen-specific CD4+ and CD8+ cells acquired effector function and proliferated with similar kinetics. CONCLUSIONS: These data extend the authors' unique transgenic transplantation model to the investigation of CD8 T cell function. The initial results confirm fundamental functional similarity between the CD4 and CD8 T cell subsets and provide insight into the considerable redundancy underlying T cell mechanisms mediating allograft rejection.     

Circadian Mechanisms in Alcohol Use Disorder and Tissue Injury

Heavy use of alcohol can lead to addictive behaviors and to eventual alcohol‐related tissue damage. While increased consumption of alcohol has been attributed to various factors including level of alcohol exposure and environmental factors such as stress, data from behavioral scientists and physiological researchers are revealing roles for the circadian rhythm in mediating the development of behaviors associated with alcohol use disorder as well as the tissue damage that drives physiological disease. In this work, we compile recent work on the complex mutually influential relationship that exists between the core circadian rhythm and the pharmacodynamics of alcohol. As we do so, we highlight implications of the relationship between alcohol and common circadian mechanisms of effected organs on alcohol consumption, metabolism, toxicity, and pathology.     

Infant communicating hydroceles—do they need immediate repair or might some clinically resolve?

Purpose

Infant hydroceles that are communicating by history (fluctuation in size) or examination (reducible fluid) are often repaired soon after presentation. We have followed a series of infant boys with such hydroceles and reviewed their early natural history.

Materials and Methods

Since 1998, we have followed 174 infant boys presenting with an apparent communicating hydrocele without immediate surgical repair. All boys were initially seen before 18 months of age and most (168) by 12 months. Most had been full term at delivery, although 32 had been premature (<37 weeks' gestational age) and 11 extremely so (<32 weeks). Most boys (120) had bilateral hydroceles at presentation.

Results

Of the 110 boys followed to disposition, 69 (62.7%) had complete resolution without surgery by a mean age of 11.7 months. Forty-one patients (37.3%) underwent surgery for correction at a mean age of 14 months because of persistence in size or development of a hernia. Six developed a hernia during observation, none of whom had any episode of incarceration. Only 2 patients with apparent resolution subsequently had recurrence with a hernia. Age at presentation and gestational age at birth showed no effect on resolution. The hydroceles of 64 boys had improved in size after a mean follow-up of 13.9 months when last seen.

Conclusions

Many infant hydroceles that are communicating by history or examination do resolve clinically without surgery and deserve observation. Progression to hernia was rare in our experience and did not result in incarceration. Consequently, little risk is taken by initial observation.