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Biomedical subjects

A D Dayan

Publications and source records attributed to A D Dayan.

At least 19 recordsLinked to original sources
PubMed2002

Carcinogenicity testing of IL-10: principles and practicalities.

IL-10 is a cytokine with actions at many levels of the immune system. In the course of development of recombinant human IL-10 (rhuIL-10) as a potential treatment for a number of chronic diseases of man, the question 'What about its carcinogenicity testing?' was repeatedly asked, based on scientific evaluation by toxicologists, beliefs about regulatory requirements, and questions considered likely to be raised by physicians, patients, and lawyers. The feasibility of various approaches to the carcinogenicity testing of rhuIL-10 is critically discussed here as a contribution to rational consideration of the general need for and value of such testing, and its particular feasibility for a recombinant human protein with profound effects on the immune system. The physiological functions of IL-10 in man and rodents are reviewed in detail, as there are notable differences between species in its normal activities, followed by detailed evaluation of the potential procedures and practical problems of its carcinogenicity testing as a heterologous, immunogenic protein in rodents. The value of information that might be obtained from transgenic mice is also evaluated, and so are the results of studies exploring its actions on human tumour cell biopsies and rodent and human cell lines. It is concluded that despite the probable popular and regulatory expectations that carcinogenicity test results would be provided, all the physiological and pathological information reveals no indication that rhuIL-10 would pose a carcinogenic risk to humans on prolonged administration, and that it would not be feasible to undertake such experimentation. It is argued that in this, as in other instances, professional and popular expectations have run beyond practical feasibility or theoretical justification. Cautious and critical evaluation should be made every time shorter or longer term toxicity studies of any candidate drug are planned or even considered, especially if it is a recombinant protein, to decide on objective grounds whether the studies are really necessary and whether they can be done in a way that will give meaningful results that will help in risk assessment.

Animals↗
PubMed2001

Mechanisms of chromium toxicity, carcinogenicity and allergenicity: review of the literature from 1985 to 2000.

Laboratory and clinical reports about the pathogenesis of the carcinogenicity and allergenicity of chromium compounds published between 1985 and 2000 have been reviewed as a basis for consideration of the pathogenetic mechanisms involved. There is good evidence from the clinic and the laboratory that Cr[VI] is the ion responsible for most of the toxic actions, although much of the underlying molecular damage may be due to its intracellular reduction to the even more highly reactive and short-lived chemical species Cr[III] and Cr[V]. Exposure to Cr[VI] can result in various point mutations in DNA and to chromosomal damage, as well as to oxidative changes in proteins and to adduct formation. The relative importance of these effects of chromium ions and of the free oxidising radicals they may generate in the body in causing tumours and allergic sensitisation remain to be demonstrated. Biochemical studies of the DNA-damaging effects and of the pathogenesis of the allergic reactions to chromium ions have not kept up with advances in understanding of the molecular basis of the effects of other carcinogens and allergens.

Allergens↗
PubMed2001

Pharmacokinetic and toxicology assessment of INTERCEPT (S-59 and UVA treated) platelets.

The pathogen inactivation process developed by Cerus and Baxter Healthcare Corporations uses the psoralen, S-59 (amotosalen) in an ex vivo photochemical treatment (PCT) process to inactivate viruses, bacteria, protozoans, and leukocytes in platelet concentrates and plasma. Studies were performed by intravenous infusion of S-59 PCT formulations +/- compound adsorption device (CAD) treatment and with non-UVA illuminated S-59, using doses that were multiples of potential clinical exposures. The studies comprised full pharmacokinetic, single- and repeated-dose (up to 13 weeks duration) toxicity, safety pharmacology (CNS, renal, and cardiovascular), reproductive toxicity, genotoxicity, carcinogenicity testing in the p53(+/-) mouse, vein irritation, and phototoxicity. No specific target organ toxicity (clinical or histopathological), reproductive toxicity, or carcinogenicity was observed. S-59 and/or PCT formulations demonstrated CNS, ECG, and phototoxicity only at supraclinical doses. Based on the extremely large safety margins (>30,000-fold expected clinical exposures), the CNS and ECG observations are not considered to have any toxicological relevance. Additionally, after a complete assessment, mutagenicity and phototoxicity results are not considered relevant for the proposed use of INTERCEPT platelets. Thus, the results of an extensive series of in vitro and in vivo studies have not demonstrated any toxicologically relevant effects of platelet concentrates prepared by the INTERCEPT system.

Animals↗
PubMed2000

Future problems requiring scientific consideration.

Water is essential for life, a precept that should control all other considerations. Water and its toxicological safety represent a paradigm for much of what is happening in other areas of society in evolving perceptions of what is 'toxicity', what is 'risk' and what we wish to or are prepared to do about such 'risks' at what cost to ourselves and others. Water is an universal solvent and may contain a wide diversity of substances arising from sources and supply systems and modified by treatment and storage. The problems that are already present, and which are closely linked to others just beginning to be recognisable, arise from the growing sensitivity of analytical techniques showing exposure to novel or ever smaller amounts of known substances in water, how to recognize and evaluate their conventional and possibly new (i.e. previously unrealized) toxic actions, how to measure exposure to water as drunk and as in foods and drinks, in what way can safe exposure levels be set, and is it feasible to people to demonstrate that 'safety' has been achieved? Behind those lie the very real problems of deciding what is 'safety', what level of notional safety do we demand in our assessments, and how do we, the people, come to realise and accept the costs that we shall have to pay in demanding any given level of 'safety'? The latter includes deciding what is an appropriate level of safety for the community as a whole and any specially susceptible groups within it. These questions are deceptively simple to pose and tortuously difficult even to attempt to answer. But they are not all the future problems. Behind them lie the socio-political uncertainties of risk and its place in society-what real or perceived risks do we accept and why, and how in a democratic society are we, the people, to be informed about risks, how should we decide what to accept or reject, and how are we to balance our beliefs and wishes against the costs of prevention or acceptance of diseases that unclean or contaminated water can bring.

Animals↗
PubMed1998

Intestinal uptake of particulate material by dexamethasone-treated rats: use of a novel technique to avoid intestinal mucosal contamination.

The aim of this study was to investigate the effect of immune suppression on the uptake of particles across the wall of the intestine and the dissemination of the particles to systemic organs. Normal and dexamethasone-immunosuppressed rats were dosed orally with 0.5 mL distilled water or fluorescent polystyrene latex particle suspension containing 2.33 x 10(9) 2-microm diameter particles. One hour after particle dosing, the animals were killed by CO2 asphyxiation. The intestinal tissues and systemic organs were sampled for particle quantitation. To avoid contamination by particles adherent to intestinal mucosa the epithelium of intestinal tissue samples was removed before quantification. The number of fluorescent particles in tissues was determined by fluorescence microscopy of digests of selected samples. The uptake of particulate material across the intestinal wall was significantly (P < 0.05) increased in rats treated with dexamethasone but the number of particles transferred to systemic organs did not differ from values found for control animals. The results suggest that although dexamethasone increased intestinal permeability the apparatus or mechanisms involved in particle transport to distal sites were not affected during immune suppression.

Administration, Oral↗
PubMed1998

Transepithelial transport of large particles in rat: a new model for the quantitative study of particle uptake.

The transport of large particles across the intestinal mucosa and the mechanisms of transfer of the particles into the body are still little understood. Fluorescent polystyrene latex particles (2 microm diam.) were administered orally to young male Sprague-Dawley rats in doses of 2.33 x 10(3), 2.33 x 10(6) and 2.33 x 10(9) particles. After 60 min, Peyer's patches and Peyer's patch-free tissues were collected from the small intestine and colon. A novel technique was used to exclude non-translocated particles adherent to the mucosal surface; the intestinal epithelium was stripped from the intestine by immersion in Hanks' balanced salt solution containing 1.5 mM EDTA. Particles in solubilized samples of intact and epithelium-stripped Peyer's patches and Peyer's patch-free intestinal tissue and colon were quantified by fluorescence microscopy. The location of particles within the intact and epithelium-stripped gut samples was revealed by confocal microscopy. Particles were shown to have been taken up along the entire length of the small and large intestines via both Peyer's patches and the normal intestinal epithelium. The number of particles detected in the distal region was greater than in the proximal part of the small intestine, although the difference was not statistically significant. This study has revealed that large numbers of non-translocated particles adhered to the mucosal surface resulting in a high background count. The assay system was considerably improved by the epithelium-stripping technique. The process of transepithelial uptake is a potentially important route of uptake of toxic, immunologically active and radioactive substances. These particles are much larger than the conventionally accepted upper limit for absorbed materials.

Administration, Oral↗
PubMed1998

Neurotoxicity and artemisinin compounds do the observations in animals justify limitation of clinical use?

High parenteral doses of certain artemisinin derivatives can produce a limited and unique, selective brain stem neuronopathy in laboratory animals. There is necrosis of a small number of nerve cells in certain brain stem nuclei and more extensive chromatolysis of neurons in the same nuclei a few days after intramuscular or intravenous injection of dihydroqinghaosu, artemether and arteether in doses exceeding about 6mg/kg/d intramuscular or intravenous for about 3-5 days (in an oily solvent) in the dog, or after a single parenteral dose exceeding about 100 mg/kg. The limited information available about the monkey suggests that it is only affected after doses several times higher. The probable order of sensitivity of species is dog > rat > monkey, but this is based on only few results. No lesions have been reported after various intramuscular and oral dosages of artesunate and artelinate. The limited reports of clinical observations have not suggested any specific pattern of abnormalities. The lesion is unique in its distribution, in the small number of neurons that become necrotic and the occurrence in nearby cells of chromatolysis. The latter is almost certainly reversible because more prolonged or higher dose studies have not shown more extensive neuronal damage. As the pathogenesis of this toxic response is not known, evaluation of the risk to man must be based on conventional assessment of active doses in animals versus those employed in the treatment of cerebral malaria. It is argued that there is no reason to anticipate a particular risk of conventional regimes employing up to artemether 3-6mg/kg/d intramuscular or other regimes involving artesunate per rectum for a few days.

Animals↗
PubMed1997

Effect of solid and liquid diet on uptake of large particulates across intestinal epithelium in rats.

The effect of diet composition on the uptake of particulates across the gastrointestinal epithelium has been examined in fasted male weanling Sprague-Dawley rats by estimating the systemic uptake of orally administered 2-microns latex polystyrene microspheres. Using a tissue solubilization assay, particle transfer in animals maintained on a fluid diet was determined. A larger number of particles was transferred from the gut lumen to the internal organs, including the mesenteric lymph node, spleen, bone marrow, liver, kidney, and heart of animals fed solid pelleted diet than those maintained on a fluid-diet 4 hr after oral administration of particles. The increase in particle number in rats fed the solid diet was only statistically significant (P < 0.05) for brain tissue in the analysis for trend. However, the number of particles retained in the proximal region of the gut at the end of this period was greater in animals fed the fluid diet. This work demonstrates that diet composition is important in gastrointestinal transepithelial translocation of microspheres.

Adolescent↗
PubMed1995

Safety evaluation of biological and biotechnology-derived medicines.

Evaluating the 'safety' of drugs produced by biotechnology resembles the assessment of conventional 'new chemical entities,' but with certain major differences. The 'quality' of the product requires careful control because of concern about the carry-over of DNA, immunogenic proteins, endotoxin and process chemicals. Equally the potency and purity of the product must also be considered, as well as its identity. The toxicity testing of rDNA-derived proteins, monoclonal antibodies and vaccines, although increasingly being swept under the umbrella of conventional studies, should be empirically devised according to the nature and physiological effects of the substance, taking account of the responsiveness of suitable species for non-clinical testing, the potential immunogenicity of heterologous proteins and any effect the drug may have on physiological mechanisms and the immune status of the test animals. Conventional types of single and multidose and reproduction toxicity experiments can then be adapted to detect and investigate any hazard of the novel drug. Kinetics, metabolism and drug interactions should be explored and the regulatory demand for genotoxicity data satisfied. If appropriate, immunological actions, including auto-immunity, can be sought. 'Safety-in-use' should then be predictable with some confidence, because of the extent of the toxicological investigations and because activities that cannot be examined will have been delineated, e.g. lack of a responsive species or of a suitable laboratory procedure.

Animals↗
PubMed1995

Translocation of particulates across the gut wall--a quantitative approach.

The translocation of latex particles across the epithelium of the rat small intestine and their transfer to internal organs was determined and quantified. The rate of particle uptake was also established. Particle uptake from the gut lumen to internal tissues was rapid as they were detected in all tissues examined within 30 minutes of oral administration. The maximum number of particles per gram tissue was detected in tissues of the small intestine. Particle number in spleen, kidney, lung, liver and brain increased with time, and in mesenteric lymph node, and heart tissues they decreased with time. Particles were also detected in bone marrow samples. These findings suggest that this animal model is useful in the evaluation and quantification of particle uptake and the determination of the tissues to where they are transported.

Animals↗
PubMed1995

[Toxicology and environment as regards their positions in society. Recognizing health risks to humans].

The nature of hazard identification and risk assessment for human health of chemicals in the environment are examined. Sources of uncertainty in the experimental approach to defining toxic hazards and risks are described and so are factors that limit the quality of many epidemiological studies of population toxicity. It is important for the toxicologist to consider all forms of risk both as probabilities and in terms of the nature and severity of the harm done to those affected. Toxicology, especially in its application to man and environmental hazards, may be influenced by societal and other politico-economic factors. Toxicologists must take care, therefore, to be recognised as true professionals, by recognising their obligations both to the proximate user of their results ad their wider responsibilities to society.

Environment↗
PubMed1994

The gastrointestinal absorption of neptunium, plutonium and americium in a primate (C. jacchus).

Mixtures of Np, Pu and Am were administered to primates (C. jacchus) by gastric intubation to measure their fractional gastrointestinal absorption (f1 values). The values obtained were about 2 x 10(-3) and 1 x 10(-3), respectively, for Np and Pu administered as the citrate, and 2 x 10(-3) and 6 x 10(-4), respectively, for Pu and Am in potato. The significance of these values in terms of absorption in humans is discussed.

Americium↗
PubMed1994

Urinary bladder hyperplasia in the rat: non-specific pathogenetic considerations using a beta-lactam antibiotic.

Eight of the known chemical substances associated with neoplasia in man are known to target the urinary bladder urothelium. Preneoplastic changes have been identified following exposure to each of these chemicals, and they have also been seen to occur in many species of lab animals. The most important such change is preneoplastic hyperplasia. Adaptive hyperplasia is the first form of hyperplasia to appear. It can be seen both in untreated controls and dosed animals. The distinguishing features are that in treated groups it does not progress with dose or time, and the process is reversible. Reparative hyperplasia involves disruption of homeostasis. Its severity increases with dose and time. It is not seen in controls but it is still reversible during the recovery segment after exposure to a toxic substance. When reparative hyperplasia continues beyond a certain threshold of time and dose, it progresses to preneoplastic hyperplasia, which further progresses with continued stimulation to frank neoplasia. The synthetic beta-lactam penem antibiotic FCE 22891 and its metabolite FCE 22101 caused adaptive urothelial hyperplasia of the urinary bladder only in rats and in no other species. Based on the pharmacokinetic profile of FCE 22891 and FCE 22101, it can be deduced that the morphologic finding of adaptive urothelial hyperplasia is caused by reduction of intravesicular urine pH. This effect has no relevance to therapeutic use in humans. Further, it is important to distinguish adaptive and reparative hyperplasia in preclinical toxicity studies.

Animals↗
PubMed1994

Effect of animal age on the uptake of large particulates across the epithelium of the rat small intestine.

A quantitative investigation into the transfer of latex polystyrene particles across the epithelium of the small intestine has been carried out using male weanling, adult and aged Sprague-Dawley rats. Orally administered polystyrene particles, 2 microns in diameter, were transferred from the lumen of the small intestine into the gut associated lymphoid tissues (Peyer's patches). No significant difference in the number of particles transported across the gut epithelium was detected between animals of different age groups. The concentration of particles detected in Peyer's patches excised from the proximal and distal regions of the small intestine of particle-treated animals did not differ significantly, except in aged rats. Particle concentration was significantly higher in Peyer's patch tissue than in adjacent Peyer's patch-free tissues of the small intestine in treated animals of all age groups. The assay method described here may be used for quantitative investigation of the transepithelial transport of large particulates.

Aging↗
PubMed1993

Allergy to antimicrobial residues in food: assessment of the risk to man.

Meat and other dietary products from food animals and farmed fish in the West may contain residues of many antibiotics and antibacterial agents, or haptenised macromolecules, e.g. penicilloylated proteins. General surveys have shown a low incidence of detectable residues in most products (up to 0.5-2%). A notable proportion of the general population has true allergic sensitivity to these substances (up to 7-10% to "penicillin") due to prior medical treatment. However, cases of proven allergy to such substances in food are extremely rare, based on clinical and laboratory proof of an immunological reaction, whereas there are less well substantiated reports blaming antibiotics in up to 50% of cases of chronic urticaria. Consideration of nature of haptenisation by antimicrobial substances, of the inefficiency of the oral route for immunisation, and of the transient and unrepeatable nature of most examples of food-related reactions all suggest that allergy to antimicrobial residues in the diet is exceedingly rare.

Animals↗