In vivo toxicity studies

In addition to the well-characterized role of iron in catalysing redox interactions, other metallic contaminants, for example, nickel, may also contribute. In vivo toxicity studies have demonstrated the capacity of nickel particulate compounds to induce tumours following intraperitoneal injection (Pott etal., 1987). Such activity is proportional to their phagocytic uptake, and to the associated respiratory burst and generation of PMN-derived reactive oxygen metabolites (ROMs), a proposed pathogenic mechanism (Evans et al., 1992a). 

The desire to achieve at least such minimal therapeutic indices and to also identify levels associated with toxicity (and the associated toxic effects) form the basis of dose selection for systemic (and most other in vivo) toxicity studies. 

Chronic in vivo toxicity studies are generally the most complex and expensive studies conducted by a toxicologist. Answers to a number of questions are sought in such a study, notably if a material results in a significant increase in mortality or in the incidence of tumors in those animals exposed to it. But we are also interested in the time course of these adverse effects (or risks). The classic approach to assessing these age-specific hazard rates is by the use of life tables (also called survivorship tables). 

In addition to screening compounds, PAMPA was recently applied for high-throughput formulation screening. For early in vivo toxicity studies, it is often necessary to rapidly develop an effective formulation to increase exposure. Such formulations are usually a combination of several excipients. Simultaneous assessment of solubility and permeability is required since formulation excipients may reduce the apparent permeability by reducing the free fraction of a drug [68]. 

ToxRefDB actor.epa.gov/toxrefdb Contains in vivo toxicity study data, mostly from EPA guideline studies of pesticides... 

Rodriguez, Escobales, and Maldonado (1994) conducted in vivo toxicity studies using murine liver slices to examine the effects of PbTx-3 on several parameters related to hepatic metabolism. The results indicated that PbTx-3 inhibited oxygen consumption and increased the intracellular Na levels and also stimulated a K+ efflux. The effect of PbTx-3 on the Na content of liver slices was negated by the Na blocker TTX, which also served to reduce the inhibition of oxygen consumption. TTX, however, did not alter the effects of PbTx-3 on the K+ movements, indicating perhaps that two distinct ion chaimels were activated by PbTx-3. 

Keniston, R.C., S. Cabellon, Jr., and K.S. Yarbrough. 1987. Pyridoxal 5 -phosphate as an antidote for cyanide, spermine, gentamicin, and dopamine toxicity an in vivo rat study. Toxicol. Appl. Pharmacol. 88 433-441. Knocke, W.R. 1981. Electroplating and cyanide wastes. Jour. Water Pollut. Contr. Feder. 53 847-851. Knowles, C.J. 1988. Cyanide utilization and degradation by microorganisms. Pages 3-15 in D. Evered and S. 

In vivo mutagenicity studies Further repeat-dose study in the rat Second developmental toxicity study Two-generation fertility study in the rat Chronic fish toxicity study Biodegradation simulation studies... 

Keniston RC, Cabellon S, Yarbrouch KS. 1987. Pyridoxal 5 -phosphate as an antidote for cyanide, spermine, gentamicin, and dopamine toxicity An in vivo rat study. Toxicol Appl Pharmacol 88 433-441. 

Although contributing limited information to the overall assessment of the repeated dose toxicity potential of a substance, studies such as acute toxicity and irritation studies as well as in vivo genotoxicity studies may provide some useful information on repeated dose toxicity. 

In vivo genotoxicity studies (Section 4.8.3) can give some indications of general toxicity based on the observations for clinical signs of toxicity. 

The various organs of the immune system such as spleen, lymph nodes, thymus and bone marrow containing the cells involved in the various immune responses offer the possibility to harvest these cells and perform in vitro assays for evaluation of effects on the immune system. When part of an in vivo animal study this may indicate a direct toxic effect of pharmaceuticals, that is, immunosuppression (Table 18.2). So, it is feasible to obtain cell suspensions for further evaluation such as determination of cellular subsets of T and B leukocytes by fluorescent activated cell sorter analysis (FACS analysis), and determination of natural killer (NK) cell activity of the spleen cell population. An advantage of this approach is that it may lead to identification of a biomarker to be used in clinical studies. In addition, in vitro stimulation of spleen cells with mitogens activating specific subsets may indicate potential effects on the functionality of splenic cell populations. Concanavalin A (Con A) and phytohemagglutinin (PHA) activate Tcells, while lipopolysaccharide (LPS) activates primarily B cell populations. Blood is collected for total white blood cell (WBC) determination and blood cell differential count. In addition, serum can be obtained for determination of serum immunoglobulins. 

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