Toxicity tests in animals: historical perspectives and new opportunities.

There is increasing interest in the use of microspheres, loaded with chemotherapeutic agents, for regional therapy to hepatic metastases. It is necessary to deliver these particles predominately to tumour rather than to normal liver. This study investigates factors influencing the distribution of regionally injected microspheres. Discreet tumour was induced in rats by subcapsular hepatic inoculations of HSN cells. At 20 days, 12.5 ftm, 25 pm or 40 pm diameter, radiolabelled albumin microspheres were administered, in various concentrations, via the gastroduodenal artery. Tumour to normal liver microsphere distribution ratios were determined and median values ranged from 0.1 (0.2mg ml-' 12.5 #Lm microspheres) to 1.8 (20mg ml 40 pm microspheres). Concentrated suspensions (20 mg ml-') of large microspheres (40 gm) produced the most favourable tumour to normal liver distribution ratios. These results not ony have implications for the therapeutic administration of microspheres but also for their use in blood-flow studies. In view of the generally disappointing results which have been reported with systemic therapy for colorectal liver meta-stases, interest has been stimulated in the concept of regional treatment. Several types of embolic particle, such as radioactive glass microspheres (Herba et al., 1988) and drug-loaded microcapsules and microspheres (Kato et al., 1981; McArdle et al., 1988), have been administered, via hepatic artery catheters, with encouraging effects. It is desirable to delivery these particles predominately to tumour, rather than normal tissues, thereby achieving maximum efficacy and minimum toxicity. Previous studies have assumed that particles, administered via the hepatic artery, are distributed in proportion to the relative arterial blood flow to the normal liver and the hepatic metastases. Furthermore , the distribution of regionally administered radiolabell-ed macroaggregated albumin has been employed to assess blood flow in tumour relative to flow in normal liver (Daly et al., 1985). However, the assumption that all embolising particles are distributed in proportion to blood flow has not been tested. Variations in size, shape, composition and concentration of microspheres or microcapsules might influence their distribution. The aim of the present study was to investigate the effects of microsphere diameter and concentration on the proportions of a regionally administered albumin microsphere bolus reaching normal liver and hepatic tumour.