Chronic tests, requirements

Partial and full fish chronics Rating sum =14, all tiers needed Testing through Phase III confirmation Chronic testing required Complete testing based on use and volume... 

However, this request of more animal testing faces several issues. There is an ethical concern on the millions of animals used every year for experiments. These tests are also those more expensive, and thus this poses questions about the costs for these experiments and the resources to cover them. Many of these tests, especially the chronic ones, require long times, years in some cases. The number of available laboratories in Europe to cover this potential request is insufficient. For all these reasons, some European regulations foresee the use of methods alternative to animal tests, such as the REACH legislation, and actually the cosmetics directive foresees the complete ban of animal tests for cosmetics by 2013. 

Under Article 7(1), if the country that receives a notification concludes that further data and information are needed for performing health and environmental assessments of the new substance, it may require the notice submitter to provide those data. This may involve completion of the Annex VII base set (for PMN s that invoke the "escape clause"), and/or performance of further tests specified in Annex VIII, in addition to those contained in Annex VII.(24) Annex VIII specifies a series of sub-chronic and chronic tests, as well as other extensive (and expensive) data requirements that may be required as a part of followup notifications once a chemical enters commercial production and its production volume increases substantially. 

In the past, major new chemicals have often had R D lead times of seven to ten years. In such cases, some aspects of newly instituted environmental assessments (e.g. a portion of the time required for long-term chronic toxicity tests) can be conducted in parallel with other R D activities. In other cases such as batch-lot production activities, new test requirements simply extend the R D cycle for the length of the test program. 

Regardless of the chemical tested and whether the test is for acute or chronic toxicity, all in vivo testing requires the reproducible administration of a known dose of the chemical under test, applied in a reproducible manner, that is generally related to the expected route of humans exposure. The nature and degree of the toxic effect can be... 

If surface scums or precipitates are observed in an acute study or the protocol requires it, the test concentrations need to be measured and documented. This requires taking appropriate samples. The investigator must have considerable expertise in taking and analyzing the samples if the concentrations are low or if sophisticated analytical techniques and/or equipment are needed. In a renewal-study or a chronic study requiring a flow-through system, it is important to take and measure test concentrations on a daily... 

Chronic toxicity Rodent and non-rodent species. 6 months or longer. Required when drug is intended to be used in humans for prolonged periods. Usually run concurrently with clinical trial. Goals of subacute and chronic tests are to show which organs are susceptible to drug toxicity. Tests as noted above for subacute. 3 dose levels plus controls. 

However, in tests of chemicals with unknown toxic characteristics, problems often arise because the actual responses of animals differ widely from those anticipated when the study was designed. To address this problem, it is prudent to increase the number of animals to ensure that animals are available at key points of a study to provide adequate information. In acute studies, the requirement for groups and number of animals in groups is related to the reliable determination of acute toxic effects and the estimation of a median lethal dose. In subchronic and chronic testing, the numbers are related to the detection of effects, providing sufficient animals for an acceptable investigation of toxic mechanisms and giving an indication of a no-effect level. ... 

Chronic toxicity data are preferred for deriving an annual average EQS (AA-EQS). Acute data are used to calculate a maximum acceptable concentration EQS (MAC-EQS) and can be used to derive the AA-EQS if insufficient chronic data are available, but an AA-EQS should not be derived exclusively on the basis of acute data. Guides to efficient decision making about the testing requirements for derivation of short- and long-term EQSs based on modes of action and other considerations were provided by Verhaar et al. (1992), de Wolf et al. (2005), and Hutchinson et al. (2006). 

LD50 is a measure of acute toxicity. Over time, many other test requirements have been added to establish safety as shown in the safety decision tree developed by the Food Safety Council (1982). In this system an organized sequence of tests is prescribed (see Figure 12-1). Other tests in this system involve genetic toxicity, metabolism, pharmacokinetics (the pathways of chemicals in the system and their possible accumulation in organs), subchronic toxicity, teratogenicity (birth defects), and chronic toxicity. To all this are added tests for carcinogenicity and... 

As we can see from Table 5.1, REACH results in a reduction of test requirements for new substances and an increase in the requirements for existing substances. Data sufficient for classifying according to acute toxicity, skin and eye irritation, and aquatic toxicity are now required for substances with production volumes above 10 t. Data sufficient to classify according to chronic toxicity and carcinogenicity are not routinely required for any of the tonnage bands, but can be required case-by-case based on initial genotoxicity tests or for substances with a yearly production above 1,000 t. 

In REACH, for chemicals produced up to 1001, it is not possible to use population modelling as an effect characterization tool since the standard tests required do not measure reproduction. However, for chemicals produced between 100 and 1,000 t, a chronic test with Daphnia is required, and for chemicals produced over 1,000 t reproduction tests with earthworms and chironomids are mandatory. For substances produced between 100 and 1,000 t, chronic tests with fish are also required, but there is currently no true reproduction test available with OECD or any other large international standardization body (however, a two-generation test is under development within OECD see Table 6.1), which means that it will not be possible to generate adequate population data for fish under current testing requirements. 

Four types of exposure conditions are employed in both acute and chronic tests and in both freshwater and saltwater media static, static-renewal (semi-static), recirculation, and flow-through. The choice for which test type to use usually depends on test substance characteristics, test duration, test species, and regulatoiy requirements. 

Chronic diseases, requiring extended testing phases to assess long-term effects, using up critical patent-protection time ... 

The FDA has made several modifications to the tests required by Part 1 of the ISO 10993 standard for the category of surface devices that permanently contact mucosal membranes. The ISO does not require acute, subchronic, or chronic implantation tests as does FDA. FDA requires irritation, systemic toxicity, acute, subchronic, and chronic tests for external communicating devices, tissue/bone/ dentin with prolonged and permanent contact. Device manufacturers are advised to consider tests to detect chemical components of device materials that may be pyrogenic. This matrix is a framework and not a checklist and it is stressed by the FDA that necessary safety testing will be decided on a case-by-case basis. 

A number of laboratory tests are available to measure exocrine function in the investigation of pancreatic insufficiency (most commonly caused by cystic fibrosis in children and chronic pancreatitis in adults). Tests fall into two categories, invasive and noninvasive. Invasive tests require GI, intubation to collect pancreatic samples noninvasive tests (or tubeless tests ) were developed to avoid intubation, which is uncomfortable for the patient, time-consuming, and therefore expensive. Noninvasive tests are simpler and cheaper to perform, but in general they lack the sensitivity and specificity of the invasive tests, particularly for the diagnosis of mild pancreatic insufficiency. It is important to recognize that biochemical tests have a limited clinical application in the diagnosis of pancreatic disease because of either the complexity of the invasive tests or the inadequate... 

The investigation of laxative abuse and measurement of fecal osmotic gap are described below. The other laboratory tests required for the investigation of chronic diarrhea are described in the sections above on intestinal disease, pancreatic diseases, and neuroendocrine tumors. 

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