Duration, toxicity tests

S4 Duration of Chronic Toxicity Testing in Animals (Rodent and Non-Rodent Toxicity Testing)... 

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, whereas in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. In the context of new chemical entities (NCEs, i.e. low molecular weight traditional chemicals), not only can the drug itself exhibit a toxic effect, but so potentially can drug breakdown products. As proteins are degraded to amino acids, any potentially toxicity associated with protein-based drugs is typically associated with the protein itself and not degradation products. 

McKim, J.M. and D.A. Benoit. 1974. Duration of toxicity tests for establishing no effect concentrations for copper with brook trout (Salvelinus fontinalis). Jour. Fish. Res. Bd. Can. 31 449-452. 

Data for PCP and terrestrial wildlife are incomplete and — in view of the large interspecies variations in sensitivity — need to be collected. Research is needed on reproductive effects in animals following inhalation exposure to PCP additional acute and intermediate toxicity testing chronic duration exposure studies on cancer induction, genotoxicity, and immunotoxicity and the development of alternate biomarkers of PCP exposure and antidotes (WHO 1987 USPHS 1994). Until the results of these studies become available, it seems reasonable to apply to wildlife the same levels recommended for human health protection. 

For similar reasons, chronic toxicity tests are probably less relevant for use in environmental risk assessment because of the significant discrepancy between the duration of exposure in the laboratory (many days to weeks) and field (usually 1 day or less - see Sect. 5). Sensitivity profiles for chronic toxicity are similar to acute toxicity, although, as would be expected, chronic endpoints are lower than the acute endpoints. Chronic toxicity endpoints for SPs are summarized in Table 3. 

Although biotechnologically derived pharmaceuticals often need customized precli-nical development programs, certain issues are common to all. These include species specificity, potential immunogenicity and its impact on the duration of dosing, and the need for special toxicity testing. 

Toxicity tests are necessary tools to evaluate the concentration and duration of exposure of a chemical required to produce certain adverse effects. Molecular processes directly affected by the exposure to the chemical agent are the most liable criterions. Nevertheless, these effects are difficult to detect in aquatic toxicology because the processes are generally not well understood [72], Alternatively, other end points which fulfil the necessary requirements, namely the need to be unequivocal, relevant, easy to observe, describe and measure, biologically significant and repeatable, are used. These include measures of mortality, which is frequently employed in the early evaluation of the toxicity of a pollutant in acute toxicity tests. This criterion allows comparison of toxicity exerted by chemical agents with very different mechanisms of action. 

S4A Duration of chronic toxicity testing in animals (rodent and nonrodent)... 

The 28-day smdies are termed repeated dose (28 days) while the 90-day smdies are termed subchronic. The chronic toxicity test (B.30), requests at least 12 months duration. The preferred species is the rat. 

The reproductive/developmental toxicity screening test can provide initial information on possible effects on reproduction and/or development and may make it possible to identify a substance as being toxic to reproduction, i.e., the test gives a clear positive result. However, this test offers only limited means of detecting postnatal manifestations of prenatal exposure or effects that may be induced during postnatal exposure. In addition, because of the study design (e.g., relatively small numbers of animals per dose level, relatively short smdy duration), the test will not provide evidence for definite claims of no effects. 

An ICH guideline entitled Duration of Chronic Toxicity Testing in Animals (Rodent and Non-Rodent Toxicity Testing) indicates that a non-rodent study of 9 months may be acceptable in the United States, Japan and EU. 

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, while in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. 

Where functional cross-reactivity to at least one of the usual toxicology species is present, and appropriate assays for PK and PD have been developed, the clinical candidate can be used in a relatively conventional developmental toxicity program with that species (preferably the rat, for which the most background data will be available). Following early sub-chronic repeat-dose toxicity testing in the rodent (usually up to 1 month s duration), with accompanying PK/PD data, the reproductive study program can be planned as appropriate to the circumstances. 

No studies on the acute toxicity of C12LAS to algae and aquatic plants were found in the literature. Typical toxicity-testing protocols use a test duration of 4-7 days. This duration of testing represents a significant portion of the organisms life span for the taxa tested. Thus these toxicity tests are appropriately considered chronic-toxicity tests. 

No Observed Effect Level (NOEL) This is the highest dose level of a chemical that, in a given toxicity test, causes no observable effect in the test animals. The NOEL for a given chemical varies with the route and duration of exposure and the nature of the adverse effect (i.e., the indicator of toxicity). The NOEL for the most sensitive test species and the most sensitive indicator of toxicity is usually employed for regulatory purposes. Effects considered are usually adverse effects, and this value may be called the No Observed Adverse Effects Level (NOAEL). 

Toxicity test/ Species study Assessment endpoint Test phased Test duration Measurement endpoint Number of replicate/ Test method reference... 

Toxicity tests Duration (days) Primary endpoints Litres of sediment required... 

Different species are used / applicable to different geographic areas. Biomarkers exampled by bacteria (Microtox ) toxicity tests can be conducted in all cases endpoint for this test is enzyme fimction, duration is hours, and amount of sediment required is minimal ( 0.1 L). 

Adequate extrapolation of results from standard laboratory toxicity tests to other time scales of exposure and response requires observations on the time course of toxic effects. These observations can then be used to construct time-to-event models, such as the DEBtox model mentioned above. These models explicitly address both intensity and duration of exposure to hazardous chemicals, and better use is made of the data gathered from toxicity experiments. Diverse endpoints in time can be addressed, and individual organism characteristics and/or environmental circumstances (e.g., temperature) can be incorporated as covariables. An overview of time-to-event models and approaches and their use in the risk assessment of chemicals is provided by Crane et al. (2002). 

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