This report is the outcome of a workshop organized by the International Life Sciences Institute-European Branch (ILSI Europe), on the "Risks of Risk Assessment in Foods" held on 18 February 1998 in Brussels, Belgium. The meeting discussed Risk Assessment as the principal means by which the European Union evaluates the potential harm arising from the use of existing and new products. The experiences of the parties involved have often shown that the concepts underlying risk assessment are complex and not always fully understood. There is an urgent need to familiarize industry, policy makers and the scientific community with developments in the basic principles and terminology of risk assessment. Therefore, the workshop aimed to review key areas in risk assessment and to provide an open forum for learning and discussion between all interested parties.

Europe↗

PubMedDate not supplied

Hemiparkinsonism with infarction of the ipsilateral substantia nigra.

An elderly man suffering from dementia associated with hypertension developed right-sided parkinsonism marked by rigidity and flexion. At autopsy the brain showed generalized vascular changes chiefly in the white matter, diffuse plaque and neurofibrillary tangle formation in the temporal cortex, and a discrete gliotic scar in the right substantia nigra. Hemiparkinsonism with a strictly unilateral lesion confined to the substantia nigra has, to our knowledge, not been described before, and the fact that it was ipsilateral adds to its theoretical interest.

Brain↗

PubMedDate not supplied

Integrating safety data: the expert report.

Complete evaluation of the toxicity of a new chemical entity requires critical analysis of the pattern of positive and negative findings in all types of toxicity tests, pharmacokinetics and metabolism in the species examined, and correlation of the effects with information about its pharmacodynamic and pharmacological properties. The goal is to obtain sufficient understanding of the mechanisms underlying the therapeutic and toxic effects of the compound to permit a well-supported extrapolation from the test to the target species. The Expert Report system in the European Community is based on comprehensive 25-page reviews of information about a compound arranged under 3 headings: Chemistry and Pharmacy, Pharmacology and Toxicology, and Clinical Studies. Each section requires a searching review of the experimental work and the relevant literature, integration of the findings, and then careful correlation among these 3 main areas of knowledge to indicate the circumstances of safe and effective use of the drug.

Documentation↗

PubMedDate not supplied

Mesenteric arteriopathy in the rat induced by phosphodiesterase III inhibitors: an investigation of morphological, ultrastructural, and hemodynamic changes.

A reproducible model of a phosphodiesterase III (PDE III) inhibitor-induced arteriopathy has been developed in the rat after subcutaneous administration of SK&F 95654. Administration of this potent PDE III inhibitor induced an arteriopathy of mesenteric arteries within 24 hr that was dose-related in intensity and incidence over the range 0.174, 0.348, 0.523, and 0.697 mmol/kg. The arteriopathy was restricted to muscular arteries of external diameter of 100-800 microns and was shown microscopically to be focal or segmental medial necrosis and hemorrhage. A time-course experiment, conducted from 3 to 24 hr postdosing, showed that the first changes observed 6 hr postdosing were on the endothelium followed by focal hemorrhages into the media at 12 hr postdosing, causing compression, degeneration, and necrosis of myocytes. From 16 hr postdosing, there was focal endothelial cell necrosis and loss of confluence. Leukocytes and activated platelets were found adhering to exposed basement lamina and seen to pass through endothelial gaps into the subintima. By 24 hr postdosing, medial necrosis was extensive with large areas of media replaced by erythrocytes, cell debris, and a few leukocytes and platelets. The effect of 3 structurally dissimilar PDE III inhibitors administered subcutaneously at a dose of 0.697 mmol/kg was compared with that of SK&F 95654. The arteriopathy induced by these compounds were identical to that produced by SK&F 95654 with the incidence and severity of lesions ranked in the following order: SK&F 95654 > WIN 62582 > SK&F 94836, with no macroscopic lesions observed for SK&F 94120. Systolic blood pressure was measured for these 4 PDE III inhibitors at regular intervals over the 24-hr period postadministration by a plesthymographic method. The severity of the arterial lesions correlated with the magnitude of hypotension induced by these agents. It is postulated that the arterial damage is a consequence of profound vasodilation resulting in abnormal endothelial permeability and increased wall tension, resulting in progressive medial necrosis and hemorrhage.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMedDate not supplied

Safety evaluation of human living skin equivalents.

Human living skin equivalents (LSEs) offer an alternative to the use of split-thickness autografts for the treatment of hard-to-heal wounds. LSEs consist of 4 active components: a well-differentiated stratum corneum derived from epidermal keratinocytes, dermal fibroblasts, and an extracellular collagen matrix. Neonatal foreskins are used as the source of keratinocytes and dermal fibroblasts for the manufacture of LSEs. Following isolation and expansion in vitro, the cells are cultured on a 3-dimensional scaffold to give an upper epidermal layer and supporting dermal layer. The resulting product has the appearance and handling characteristics of human skin. Safety evaluation of LSEs begins with insuring that foreskins are obtained only from healthy infants whose mothers are negative for a panel of adventitious agents. Keratinocyte and fibroblast cell banks are characterized using morphologic, biochemical, and histologic criteria; checked for the absence of contaminating cell types such as melanocytes, macrophages, lymphocytes, and Langerhans cells; subjected to rigorous microbiological testing (with any production materials of biological origin); and evaluated for in vivo tumorigenicity. The consistency of certain key morphologic and functional characteristics are regularly assessed. Because an LSE represents an allogeneic graft, preclinical safety studies include in vitro and in vivo determinations of its potential immunogenicity. Immunocompromised (SCID) mice reconstituted with human leukocytes or engrafted with human fetal hematolymphoid organs have been useful animal models for assessing possible immunologic responses to LSEs. Additional preclinical studies are being conducted to show that LSEs are noncytotoxic and lack allergenic, sensitizing, or irritation potential.

Animals↗

PubMedDate not supplied

Development immunotoxicology and risk assessment. Conclusions and future directions: a personal view from the session chair.

Developmental immunotoxicity is new both as an area of scientific study and as a potential source of concern in the protection of the public health. It is a combination of three nascent sciences and one older established area of study--immunology, 'Development', toxicological science and the practical application of experimental findings to indicate risks to man and means to control them. This hardworking and very successful meeting, organized by the Immunotoxicology Technical Committee (ITC) of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) with input from the U.S. Environmental Protection Agency (EPA), provided an appropriate setting in which scientists from industrial, academic and regulatory backgrounds were able to debate how the development of the immune system might be affected by toxicity, and ways in which transient and permanent harmful effects might occur. There was considerable interest in how the basic processes and structures of immunity and development might be affected by model substances, which could afford examples to demonstrate the value of laboratory methods to detect developmental immunotoxicity. There were vigorous discussions about testing strategies, about techniques, about how to 'validate' laboratory methods when there was relatively little consistent information from man to identify suitable positive control substances and cardinal disorders, and about how best to employ the sparse information to support the effective prediction of risk.

Animals↗