A.D. Dayan

Dominant lethal study of ribavirin in male rats

Ribavirin, a new synthetic antiviral agent, was studied for dominant lethal effects in male CD rats. The drug was administered intraperitoneally at doses of 50, 100 and 200 mg/kg/day for 5 days. Males were mated weekly with 8 consecutive batches of female rats. Marginal increase in early foetal death detected in Assessment Weeks 3 and 8 in females mated with the low-dose and high-dose males were not dose-related and were most probably chance events caused by the particularly low vehicle control frequencies for these 2 weeks. Also, the slightly reduced pregnancy proportion among females mated with the high-dose treated males was to a substantial extent the effect of a single male rate which failed to fertilize any females. Ribavirin was, therefore, regarded as being devoid of any mutagenic potential demonstrable by a rat dominant lethal assay.

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 rhuIL10 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.

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.

Effects of a cholecystokinin receptor antagonist on rat exocrine pancreatic response to raw soya flour

1 Raw soya flour (RSF) in the diet induces pancreatic hypertrophy and hyperplasia in the rat, changes ascribed to production of a high circulating level of cholecystokinin (CCK) due to inhibition of trypsin in the duodenum. Prolonged ingestion results in pancreatic adenomas and carcinomas. 2 L-364, 718, a potent, highly specific CCK antagonist was used to investigate the short-term role of CCK. 3 In rats fed 50% RSF and L-364, 718 5 mg kg-1 p.o. twice daily for 4 d, there was inhibition of pancreatic hypertrophy and hyperplasia, which is further evidence that peripherally-acting CCK plays a major role in the generation of RSF-mediated changes in the pancreas.

Single Dose Toxicity

These guidelines deal with the qualitative and quantitative study of toxic phenomena and their occurrence related to time after a Single administration of the substance, or combination of substances.

Organophosphorus Pesticides and Human Health Abstracts of a Meeting Organized by Dr T.C. Marrs and held in London, 6 March 1992

The first and last presentations were on the fundamental toxicology of organophosphorus pesticides (OPs), covering inter alia the ways in which OPs inhibit acetylcholinesterase and the acetycholine receptor, which must have a stereochemically related active site. The biochemical mechanism of the enzyme inhibition had been extensively studied (it was part of the developmental history of biochemical toxicology), and the nature of the

A Clinical Scientist's View of Preclinical Drug Testing Requirements

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Strength of Meaning—Strong Words and a Certain Message?

The ability to convey specific meanings is important to scientists in their writing. However, difficulties arise when the ideas to be portrayed are judgemental. While extreme terms expressing strength of meaning are readily understood, more subtle ones appear not to be.

How Should We Regard Risks

Toxicology and toxicologists are both used and abused in proposing levels of ’risk’ that ultimately form the bases of practical decisions about the acceptability of chemicals as drugs, and in industry, at home and in the environment. That should be acceptable, as a legitimate goal of applied toxicology, but grave philosophical, scientific and even geographical uncertainties lie concealed in the simple syllogism that is commonly implied define the toxic hazard and its dose-response relationship, consider exposure to the causative substance, and then predict the risk. 1 Unless these uncertainties are clearly understood, there can only be increasing disagreement about risk acceptance in the public

The Toxicological Background

Toxicity testing in the early phases of drug development has three main purposes: (1) to demonstrate toxic effects and the circumstances of their occurrence; (2) to show what toxic effects did not occur; (3) to suggest whenever possible the likely mechanisms of toxicity. From all these findings and analyses, a cautious prediction can be made of the possible nature and incidence of toxic effects in man, so that likely risks can be matched against anticipated benefits of treatment.