Toxicity Findings

A complex series of in vitro tests, animal test and then human exposure can at any stage reveal adverse findings that can be termed toxicity. Broadly, toxicity findings can be broken down into the following three sub-divisions. 

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A governing principle of pharmaceutical safety assessment is the determination of safety factors the ratio between the therapeutic dose (that which achieves the desired therapeutic effect) and the highest dose which evokes no toxicity. This grows yet more complex (but has less uncertainty) if one bases these ratios on plasma levels rather than administered doses. Traditionally based on beliefs as to differences of species sensitivity, it has been held that a minimum of a five-fold (5X) safety factor should be observed based on toxicity findings in nonrodents and a ten-fold (10X) based on rodents. 

Chronic and subchronic toxicity studies are conducted to define the dose level, when given repeatedly, that cause toxicity, and the dose level that does not lead to toxic findings. In Japan, such studies are referred to as repeated-dose toxicity studies. As with single-dose studies, at least two animal species should be used, one rodent and one nonrodent (rabbit not acceptable). In rodent studies, each group should consist of at least 10 males and 10 females in nonrodent species, 3 of each sex are deemed adequate. Where interim examinations are planned, however, the numbers of animals employed should be increased accordingly. The planned route of administration in human subjects is normally explored. The duration of the study will be dictated by the planned duration of clinical use (Table 2.14). 

The study of absorption, distribution, metabolism and excretion in toxicology studies, usually referred to as toxicokinetics, provides extremely useful information on the pharmacokinetics of high doses and of repeated doses of the compound. The dose dependency of the pharmacokinetics and the possible time effects, e.g. a decrease in exposure over time as a result of enzyme induction, is essential information for the interpretation of the toxicity findings as well as for the planned clinical studies. 

From a regulatory perspective, an observed developmental toxic finding is considered to be of potential human relevance (even if it is mediated via maternal pharmacological effects or occur at doses causing signs of maternal toxicity) unless the company can provide appropriate mechanistic and/or other convincing evidence to the contrary. 

Sasaki J, Chapin R, Hall D, Breslin W, Moffit J, Saldutti L, Enright B, Seger M, Jarvi K, Hixon M, Mitchard T, Kim JH (2011) Incidence and nature of testicular toxicity findings in pharmaceutical development. Birth Defects Res B Dev Reprod Toxicol 92(6) 511-525. doi 10.1002/bdrb.20338... 

Comparative Toxicokinetics. There are currently not enough data to evaluate any potential species-related differences in response to radium exposure by any route. It would be useful to have information on which animal models most closely approximate humans in this regard in order to help interpret the relevance to humans of any toxicity findings in animal studies. Studies on the toxicokinetics of radium following inhalation, oral, and dermal exposure are needed to compare the different routes of exposure. 

Scroggins, R.P., Miller, J.A., Borgmann, A.I. and Sprague, J.B. (2002b) Sublethal toxicity findings by the pulp and paper industry for cycles 1 and 2 of the environmental effects monitoring program, Water Quality Research Journal of Canada 37 (1), 21-48. 

In Note 8 of the ICH Guidance Toxicokinetics 1994 it is stated It is often considered unnecessary to assay samples from control groups. Samples may be collected and then assayed if it is deemed that this may help in the interpretation of the toxicity findings, or in the valida-... 

There are no human data on the effects of JP-8 on development. The animal data are sufficient to conclude that prenatal oral exposure at doses of 1,500 mg/kg/d and greater administered on gestation days 6-15 in rats causes developmental toxicity. These toxicity findings in rodents are assumed to be relevant for prediction of risk to humans. 

Regarding toxicity findings, the meanings in clinical use must be considered and inserted in the package insert if necessary. If there is previous demonstration of specific side effects in the same product class, safety regarding that side effect must be evaluated. 

Toxicity test results expressed in terms of harm to living organisms are more credible or comprehensible than chemical data to non-specialists (Sergy, 1987). They can also be less expensive than comprehensive chemical analysis. However, a toxic finding could be misleading if used in a simplistic way, e.g. failing to allow for dilution or mitigating factors. 

While the scientific basis for risk assessment has been described in the previous chapters, certain critical issues were left up in the air. Scientists have not yet been able, for example, to establish with certainty the relevance to humans of animal toxicity findings, and generally have poor or even no empirical data regarding dose-response relations at the human dose levels typically associated with environmental chemicals. Moreover, toxicity data gaps of one sort or another exist for all chemicals sometimes the gaps are not of great importance, but often they will seriously hamper the risk assessment process. So, while risk assessors may know much, they are always faced with significant scientific uncertainties. Indeed, some observers think risk assessment is best described as the analysis of uncertainty. 

The size and quality of the batch of bulk chemical or biological material that will be formulated for the first study in man are critical to the expeditious transfer from animals to man. Wherever possible, the same batch that has been used for toxicology should be used for the human studies. This avoids difficulties in attributing toxicity findings to different impurities or different proportions of the same impurities that are frequently encountered in early batches. Although the batch size may be limited, the amount of material required for the initial human studies is generally small compared with that used for toxicology. 

A Discussion and Conclusions subsection on the toxicology results allows a sponsor s author to discuss the toxicity findings with reference to the significant issues that were noted or observed. The use of in-text tables and figures for highlighting these findings is recommended. 

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