Lipidic toxicity evaluation

Peroxidation of lipids is another factor which must be considered in the safety evaluation of liposome administration. Smith and coworkers (1983) demonstrated that lipid peroxides can play an important role in liver toxicity. Allen et al. (1984) showed that liposomes protected by an antioxidant caused less MPS impairment than liposomes subjected to mild oxidizing conditions. From the study of Kunimoto et al. (1981) it can be concluded that the level of peroxidation in freshly prepared liposome preparations and those on storage strongly depends both on the phospholipid fatty acid composition and on the head group of the phospholipid. Addition of appropriate antioxidants to liposomes composed of lipids which are liable to peroxidation and designed for use in human studies is therefore necessary. 

The physico-chemical properties may provide indications about the absorption of the substance for various routes of exposure and may therefore be of importance in the evaluation whether an appropriate administration route has been applied in the available experimental toxicity studies. In order for a substance to be absorbed, it must cross biological membranes. Most substances cross biological membranes by passive diffusion. This process requires a substance to be soluble both in lipid and water. The most useful parameters providing information on the potential for a substance to diffuse across biological membranes are the logPoctanoi/water and the water solubility. 

Table 7 Example application of process in Box B to evaluate the risk of dioxins in Dutch sediments. No observed effect (NOEC) concentrations for chronic toxicity of dioxins in vertebrates (immune, reproductive and developmental toxicity) expressed as internal concentration (ng TEQ/g Iw). The sediment to fish bioconcentration factor is set at 4 (ng TEQ/g Organic Carbon to ng/g lipid weight in fish) based on Traas et al. (2001). Based on a species-specific biomagnification factor (BMP) from fish to animal (ng TEQ/g Iw) the internal NOEC is extrapolated to a NOEC in sediment. These data are used to construct the SSDs in Figures 5 and 6.

It is not surprising then that, despite its effectiveness, methotrexate therapy is underscored by serious side-effects and problems which have prompted ongoing research programmes to attempt the preparation of new analogues possessing better tumour-cell selectivity, lower toxicity, better transport properties, and improved lipid solubility and membrane permeability. These efforts have resulted in the preparation of thousands of analogues in which virtually every major area of the molecule has been varied and evaluated. 

For adequate toxicologic evaluation, determinations should be made on lipids, hormones, acid/base balance, methemoglobin, and cholinesterase activity. In other words, additional clinical biochemistry may be resorted to wherever necessary to arrive at meaningful conclusions in association with the observed effects. Urinalysis, although not required on a routine basis, should be performed whenever there is an indication based on observed toxicity. 

Goodglick LA, Pietras LA, Kane AB. 1989. Evaluation of the eausal relationship between erocidolite asbestos-induced lipid peroxidation and toxicity to macrophages. Am Rev Respir Dis 139 1265-1273. 

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