The OECD program to validate the rat uterotrophic bioassay to screen compounds for in vivo estrogenic responses: phase 1.

The Organisation for Economic Co-operation and Development has completed the first phase of an international validation program for the rodent uterotrophic bioassay. This uterotrophic bioassay is intended to identify the in vivo activity of compounds that are suspected agonists or antagonists of estrogen. This information could, for example, be used to help prioritize positive compounds for further testing. Using draft protocols, we tested and compared two model systems, the immature female rat and the adult ovariectomized rat. Data from 19 participating laboratories using a high-potency reference agonist, ethinyl estradiol (EE), and an antagonist, ZM 189,154, indicate no substantive performance differences between models. All laboratories and all protocols successfully detected increases in uterine weights using EE in phase 1. These significant uterine weight increases were achieved under a variety of experimental conditions (e.g., strain, diet, housing protocol, bedding, vehicle). For each protocol, there was generally good agreement among laboratories with regard to the actual EE doses both in producing the first significant increase in uterine weights and achieving the maximum uterine response. Furthermore, the Hill equation appears to model the dose response satisfactorily and indicates general agreement based on calculated effective dose (ED)(10) and ED(50) within and among laboratories. The feasibility of an antagonist assay was also successfully demonstrated. Therefore, both models appear robust, reproducible, and transferable across laboratories for high-potency estrogen agonists such as EE. For the next phase of the OECD validation program, both models will be tested against a battery of weak, partial estrogen agonists.

Alkaline diuresis for acute poisoning with chlorophenoxy herbicides and ioxynil.

The relation between blood chlorophenoxy herbicide and ioxynil concentrations and toxicity, and the effect of alkaline diuresis on outcome, have been studied in 41 patients. More than one herbicide was found in 38 cases. 6 of 30 patients who had ingested chlorophenoxy compounds alone died; 16 patients (mostly in grade 3-4 coma) had alkaline diuresis and 15 survived. 7 of 11 patients who had co-ingested ioxynil died; 3 had alkaline diuresis and all survived. Alkaline diuresis reduced plasma chlorophenoxy half-lives to values observed after doses that had no adverse effects (ie, below 30 h), but did not influence ioxynil clearance. Alkaline diuresis should be used to treat acute poisoning with chlorophenoxy herbicides or ioxynil in the presence of coma or other poor prognostic indicators, such as acidaemia, or if plasma total chlorophenoxy concentrations are 0.5 g/l or more.

The epidemiology and prevention of paraquat poisoning.

In the UK there was an increase in the annual number of deaths associated with paraquat poisoning between 1966 and 1975. Since that time there has been little change in numbers. High mortality is associated commonly with suicidal intent. Serious accidental poisoning from paraquat has never been frequent in the UK and there have been no deaths reported in children since 1977. The National Poisons Information Service has monitored in detail all reports of paraquat poisoning since 1980. Of the 1074 cases recorded there were 209 deaths. In recent years serious poisoning has been more commonly associated with ingestion of concentrated products by males. Local exposure to paraquat has not resulted in systemic poisoning. International data for paraquat poisoning is incomplete and difficult to compare. There is a scarcity of morbidity data at both international and national levels. Information obtained from Poison Control Centres indicates that paraquat poisoning occurs in many countries but detailed comparisons are hindered by lack of standardised methods of recording. Various measures to prevent paraquat poisoning have been introduced. Their effectiveness has not been studied in detail. Some support is provided by the low incidence of serious accidental paraquat poisoning in the UK, but because of the suicidal nature of paraquat poisoning it is unlikely that current preventative measures will influence the number of deaths occurring each year. Preventative measures against paraquat poisoning should be tailored to national needs, based on and assessed by epidemiological studies.

Dianthins, ribosome-damaging proteins with anti-viral properties from Dianthus caryophyllus L. (carnation).

1. Dianthin 30 and dianthin 32, two proteins isolated from the leaves of Diathus caryophyllus (carnation), were purified to homogeneity by chromatography on CM-cellulose. 2. The mol.wt. of dianthin 30 is 29 500 and that of dianthin 32 is 31 700. Both dianthins are glycoproteins containing mannose. 3. Dianthins inhibit protein synthesis in a lysate of rabbit reticulocytes, with an ID50 (concentration giving 50% inhibition) of 9.15 ng/ml (dianthin 30) and 3.6 ng/ml (dianthin 32). They act by damaging ribosomes in a less-than-equimolar ratio. Protein synthesis by intact cells is partially inhibited by dianthins at a concentration of 100 microgram/ml. 4. Dianthins mixed with tobacco-mosaic virus strongly decrease the number of local lesions on leaves of Nicotiana glutinosa.

Inhibition of protein synthesis by a toxic lectin from Viscum album L. (mistletoe).

1. The haemagglutinating and toxic lectin from Viscum album L. (mistletoe) inhibits protein synthesis in a lysate of rabbit reticulocytes, with an ID50 (concentration giving 50% inhibition) of 2.6 microgram/ml. This effect is enhanced (ID50 0.21 microgram/ml) if the lectin is reduced with 2-mercaptoethanol. 2. The lectin inhibits protein synthesis also in BL8L cells in culture. Inhibition occurs after a lag time of 3 h. The ID50 is 7 ng/ml, and increases after reduction of the lectin. 3. This and the gross lesions observed in rats poisoned with V. album lectin indicate this is a toxin very similar to ricin.