Information Derived from Toxicity Testing

Several important characteristics can be gleaned from toxicity testing and used to assess human health risk (Chapter 8) and ecological risk (Chapter 9). 

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The acute dermal irritation is the study of reversible inflammatory changes in the skin of test animals following the application of a test chemical. Acute dermal corrosion is the study of irreversible tissue damages in the skin following the application of a test chemical. In the evaluation of toxic characteristics of a chemical, determination of the irritant or corrosive effects on mammal skin is an important study step. Information derived from this test indicates the existence of hazards likely to arise from skin exposure to the test chemical. 

Raw toxico-kinetic values, those derived directly from toxicity test data, were converted to the more familiar bioconcentration-based kinetic values by using the relationship between the internal toxicant concentrations associated with the completion of toxicity and bioconcentration tests. Simple kinetics information is based on the estimated internal dose. Given that the internal dose for acutely toxic narcotics appears to be constant while the internal dose for bioconcentration of those same chemicals increases with increasing log then it is hypothesized that the difference in the internal concentration endpoints, which is explained by Kg, can be used to convert kinetic data between the two test procedures. 

In vitro developmental toxicity systems have clearly been usefid for studies of mechanisms of developmental effects (e.g., Datson et al., 1989) — use (3) in the list above. It is unclear, though, whether in vitro developmental toxicity tests will provide useful information about developmental toxicity that is not derived from whole animal studies [use (4) from the list]. As is true for a possible use as a prescreen, the interpretation of a positive finding in an in vitro test will depend on knowing the exposure level in vivo. When this is known, the in vitro information could be helpful. The results of in vivo studies, though, would still likely be considered definitive for that species. 

The use of animals for pharmacological and toxicological studies has yielded invaluable information for drug development. However, many drug candidates failed in Phase I and II clinical trials because the animal models were insufficient to represent human systems and functions for some drugs. Efficacy and acceptable toxicities derived from animal models were not replicated in humans (Exhibit 5.8). In recent years, the direction in development of drugs has shifted toward the use of ex vivo, in vitro assays and even in silico methods. Nevertheless, some tests must stiU be confirmed in animals. 

As mentioned above, a NOAEL can usually not be derived from the classic test guideline methods for skin and eye irritation. Based on information from acute and/or repeated dose toxicity smdies using inhalation, it may be possible to derive a NOAEL and/or LOAEL for respiratory tract irritation. In such smdies, the slope of the dose-response curve is a particularly useful parameter as it indicates the extent to which reduction of exposure will reduce the irritative response the steeper the slope, the greater the reduction in response for a particular finite reduction in exposure. 

Because information on possible long-term effects of the other irritant chemicals used in the Edgewood tests is sparse, this chapter focuses on the effects of mustard gas and two lacrimators, CS and CN. Information on the potential long-term adverse effects of these chemicals is derived from several sources first, observation of long-term disabilities in soldiers who were exposed to a single (in most cases) toxic concentration of irritant during World War I and in persons exposed in peacetime accidents or riot-control procedures second, studies of morbidity in workers chronically exposed to chemical irritants during their manufacture and third, studies in which experimental laboratory animals were exposed to selected chemicals by topical application, injection, or aerosol inhalation. 

Because, for regulatory purposes, the most important information needed concerns chronic toxicity, little useful information is derived from the LD50 test. The small amount of information that is acquired could be obtained as well from an approximation requiring only a small number of animals. 

The primary information on experimental animal testing for reproductive and developmental toxicity potential is likely to be derived from standard studies used by regulatory agencies. Several statutes... 

A similar application of ecotoxicological data is hazard assessment. Unlike risk assessment, hazard assessment is nonprobabilistic and relies upon indices rather than probabilities. One such index is the hazard quotient , which is the ratio of the expected environmental concentration (based upon field surveys or simulation models) divided by a benchmark concentration. The benchmark concentration is derived from some measure of toxicity such as the LC50 or no-observed-effect level. Hazard assessments are often conducted at different levels or tiers of increasing complexity and specificity if a chemical is identified as potentially hazardous by tier (the least complex and specific test), a decision is made to take action or, if more information is needed, to proceed to tier 2 tests. After tier 2 tests, a decision is made whether to take action or proceed to tier 3 tests, and so on. This process is repeated until it is decided that there is enough information to determine whether or not there is significant ecological hazard. If there is, then regulatory action is taken. 

Next, it is important to consider whether the width of the 95% CIpred from the alternative method is small enough to provide an acceptably precise prediction of in vivo toxicity. The analysis presented earlier demonstrated that the 95% CIpred from an alternative method might be large. A benchmark that can be used to assess the acceptability of a large 95% CIpred could be derived from an examination of the precision of toxicity measurements obtained from the in vivo toxicity test. If an alternative method provides predictions as precise as those obtained from the in vivo method it is intended to replace, then it would provide evidence that the 95% CIpred alternative method is acceptable (for more information on the utility of the 95% CIpred)-... 

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