Tissue toxicity tests

S3B Pharmacokinetics Guidance for Repeated Dose Tissue Distribution Studies Toxicity Testing... 

Although the initially reported tissue compatibility tests for subcutaneous implants of poly(BPA-iminocarbonate) were encouraging (41,42), it is doubtful whether this polymer will pass more stringent biocompatibility tests. In correspondence with the properties of most synthetic phenols, BPA is a known irritant and most recent results indicate that BPA is cytotoxic toward chick embryo fibroblasts in vitro (43). Thus, initial results indicate that poly(BPA-iminocarbonate) is a polymer with highly promising material properties, whose ultimate applicability as a biomaterial is questionable due to the possible toxicity of its monomeric building blocks. 

Since disinfectant itself might be toxic to the tissue culture or eggs, a toxicity test must also be carried out. Here, appropriate dilutions of disinfectant are mixed with inactivated horse serum and inoculated into tissue cells or eggs (as appropriate). These are examined daily for damage. 

The kidney and liver are the primary target organs for hexachloroethane based on the results of toxicity testing and supported by toxicokinetic information from tissue distribution and binding studies (Lattanzi et al. 1988). Male rats were more susceptible to kidney damage than female rats (NTP 1989), and the kidneys of male rats contained 4-45% more hexachloroethane radiolabel than the kidneys of female rats (Gorzinski et al. 1985). However, there were some effects on kidneys of both sexes. 

Is there sufficient systematic toxicity data available at levels that demonstrate adequate exposure If a study was designed such that there was insufficient exposure or duration of exposure to potential lymphoid target tissues, the test protocol may not be adequate to demonstrate an adverse effect. 

The Clonetics cell line from Cambrex Bio Science represents a cultured human corneal epithelial model (order no. CMS-2015 Cambrex Bio Science, Walkersville, MD). The culture model was generated by isolation of cells from normal human corneal tissues. The cells were then infected with an amphotropic recombinant retrovirus containing HPV-16 E6/E7 genes to extend the useful cell life span. The Clonetics cell model is a very recent entry into the immortalized corneal cell line field, but it has been proved to be useful for toxicity testing as well as in vitro drug permeation studies so far. Because of its very recent introduction, further examinations have to be undertaken to... 

So the animals used in the toxicity test, both treated and control animals, are subjected to extremely thorough medical monitoring, even to the point of sacrificing their lives so that the toxicologist can learn in minutest detail whether any of their tissues have been damaged. Obviously, there is no way such thorough information could ever be collected from any imaginable study of humans exposed to chemical substances. 

Toxicity studies in animals have failed to show evidence of damage in any tissue examined after 3 months administration to rats of daily doses up to 20 000 times that required to produce diuresis. Similar absence of effect on all vital organs was found in dogs and rhesus monkeys. No teratogenesis or impairment of fertility was detected. Very large doses (up to 10 000 mg/kg) failed to produce ill-effects in acute toxicity tests on rats, though intravenous LDjo values were in the region of 230 mg/kg. 

In each microtiter plate, quadruplicate samples of known toxic (positive) and nontoxic (negative) control fish tissues were tested in parallel with the unknown samples. 

As part of the assessment of reproductive toxicity testing there is a regulatory requirement that fetuses from treated dams are examined for developmental and structural abnormalities by soft tissue examination. Current guidelines (1, 2) stipulate that this is performed in two laboratory species, one rodent (rat or mouse) and one non-rodent (routinely rabbit), in order to assess the safety of a test compound before, or in case, humans are exposed. 

Mucous membrane tissue lining of nose, mouth, esophagus, stomach, and intestine. Multigeneration Study A toxicity test in which at least three generations of the test organism are exposed to die chemical being assessed. Exposure is usually continuous. 

Table 21.6 Tissues and Organs to Be Examined Histologically in Chronic and Subchronic Toxicity Tests...

Measurement endpoints for each of the LOE (chemistry, toxicity, benthic community, biomagnification) should adequately represent the respective assessment endpoints (e.g., chemicals measured include toxicants actually present testing involves appropriate fauna that can be affected by those toxicants). In some cases direct measurements are possible (e.g., number of species, types of species). In other cases inferences are necessary (e.g., between toxicity tests and alterations in benthic communities between tissue body burdens and biomagnification potential). 

TIE and CBR analyses are conducted as appropriate. CBR analyses can be conducted, depending on the contaminant, as part of the biomagnification LOE (measuring contaminants in tissues of field collected organisms, e.g., Hg), or as part of the toxicity LOE (measuring contaminant concentrations in tissues of toxicity test organisms, e.g., other metals). TIE analyses are typically conducted following a determination of toxicity, in that LOE. 

When methods of toxicity testing were first developed most biochemical and physiological determinations required large samples of tissue. Traditionally, toxicologists have used the rat for this... 

Tissue Cross-Reactivity Studies for Monoclonal Antibodies Predictive Value and Use for Selection of Relevant Animal Species for Toxicity Testing... 

Animal tissues are collected at necropsy of humanely euthanized, purpose-bred laboratory animals immediately following death. Some nonhuman primates used for tissue acquisition may be wild caught. The animals used are preferably matched as closely as possible to that of the strain or origin of the animals to be used for preclinical toxicity testing. 

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