Toxicity studies definitive

FMC. 1990a. Non-definitive acute oral toxicity study of Durad 110 in rats. Study No. 190-1143. FMC Corporation, Princeton, NJ. 

Shuman and Michael [10] applied a rotating disk electrode to the measurement of copper complex dissociation rate constants in marine coastal waters. An operational definition for labile and non-labile metal complexes was established on kinetic criteria. Samples collected off the mid-Atlantic coast of USA showed varying degrees of copper chelation. It is suggested that the technique should be useful for metal toxicity studies because of its ability to measure both equilibrium concentrations and kinetic availability of soluble metal. 

FIGURE 5.13. The design and conduct of a supplemented (or heavy ) acute systemic toxicity study. The figure illustrates the approach to such a study when it is to serve as the definitive systemic toxicity study for some period of time. 

In the test guidelines for 90-day dermal (OECD TG 411) and inhalation (OECD TG 413) toxicity studies, the following definition in relation to the term subchronic is provided Subchronic dermal/inhalation toxicity is the adverse effects, which follow repeated daily dermal application/ inhalation of a chemical for part (not exceeding 10%) of a life span. ... 

Single-dose toxicity studies fall into two categories preliminary and definitive studies. Preliminary studies are performed to provide an estimate of the maximum nonlethal dosage (MNLD) for use in definitive studies. Definitive studies are performed to evaluate effects that may result from acute exposure to the MNLD and predict effects of overdosage in man. 

Data from repeat-dose toxicity studies are essential for CTAs in the early stages of development of a compound, but are superseded once there is a reasonable amount of human data. Any target organs that are identified in the toxicity studies should be monitored in clinical trials. Definitive data on the effects derived from clinical trials will show whether the animal studies are predictive of the effects in humans. This information can then be used to help interpret findings in reproductive toxicity studies, such as whether general toxicity in the adult is relevant. If adult toxicity in animals is deemed relevant, the exposure at which it occurs can be used to estimate the clinical relevance of any reproductive effects. If toxic effects in animals are induced at exposures greatly in excess of the clinical exposure, then they might not be clinically relevant. 

Just as qualitative judgments of toxicity are made using a reference point on the metabolism rate-concentration relationship, quantitative evaluation of toxicity is also made with respect to a reference point. It would seem that the definition of the point of reference for quantitative evaluation should be more exact than that used for qualitative judgment. Unfortunately, this is not the case for waste treatment system studies. In virtually all quantitative toxicity studies, the performance of units containing added quantities of the substance under study is compared with the performance of a control unit. Invariably, the control unit is one which exhibits satisfactory biological activity and to which none of the substance under study has been added. Very rarely is the concentration of the substance under study established or fixed in the control. 

There is evidence that the only volatile compound of Otto Fuel II, propylene glycol dinitrate, is absorbed following exposure. Also, there is evidence for dermal or oral absorption from toxicity studies but no definitive toxicokinetic work has been done. 

For all these reasons, PBPK models are and will continue to be increasingly used in toxicology. This is especially true in risk assessment studies since better definition of the internal tissue dose, may contribute to reduce the uncertainty associated with extrapolation to human beings of responses observed in animal toxicity studies in which animals usually receive high doses of xenobiotics by routes often different from the one(s) anticipated in human exposures. 

The proposed US EPA weight-of-evidence (WOE) scheme for suspect developmental toxicants defines three levels of confidence for data used to identify developmental hazards and to assess the risk of human developmental toxicity (1) definitive evidence for human developmental toxicity or for no apparent human developmental toxicity, (2) adequate evidence for potential human developmental toxicity or no apparent potential human developmental toxicity, and (3) inadequate evidence for determining potential human developmental toxicity. The scheme may require scientific judgment based on experience to weigh the implications of study design, statistical analyses, and biological significance of the data. 

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