Tiered approach to testing

In view of these complexities, environmental studies that seek to verify proposed cause-effect relationships between contamination and response need to be carefully designed to avoid bias and misunderstanding. Most environmental assessments adopt a multi-tiered approach to testing, in which combinations of biological responses (biomarkers) are measured in tissue samples, body fluids or at the whole organism level to indicate exposure to or adverse effects of contamination.8. Auffret and colleagues60 surveyed Pacific oysters from the Atlantic coast of Brittany after the Erika oil spill between... 

Kinter and Dixon (1995) described a safety pharmacology program for pharmaceuticals wherein they advocated for a tiered approach to testing drug effects on major organ functions ... 

The basis of the recommended approach to a hazard assessment of the potential immunotoxicity of a substance is that many immunotoxic substances can be identified via the standard tests for systemic toxicity. Special smdies to characterize effects of concern for immunotoxicity are used only when necessary for adequate hazard assessment. The nature of special smdies, and when they should be conducted, need to be decided on a case-by-case basis. A tiered approach to the identification of immunotoxic hazard in routine toxicology is described in WHO/IPCS (1996). 

Cooper RL, Lamb JC, Barlow SM et al (2006) A tiered approach to life stages testing for agricultural chemical safety assessment. Crit Rev Toxicol 36(l) 69-98... 

Hurtt ME, Cappon GD, Browning A (2003) Proposal for a tiered approach to developmental toxicity testing for veterinary pharmaceutical products for food producing animals. Food Chem Toxicol 41 611-619... 

Chapter 18 The Tiered Approach to Toxicity Assessment Based on the Integrated Use of Alternative (Non-animal) Tests Andrew P. Worth... 

The tiered approach to hazard classification was evaluated by simulating possible outcomes obtained when a stepwise strategy comprising three alternative tests and one animal test (Figure 18.2) is applied to a heterogeneous set of 51 chemicals (Table 18.7). The decision rules in steps 1 to 3 are based on the CMs for skin corrosion developed above. 

A tiered approach to the evaluation of initial information should be considered where applicable, recognizing that all elements may not be relevant in certain cases. The tiered approach explained in Figure 3.3.1 was developed with contributions from (inter)national centres and committees for the testing and validation of alternatives to animal testing during a workshop in Solna, Sweden. ... 

A weight-of-evidence or tier approach to the level of suspicion of carcinogenic risk will be the main objective, and will include SAR and findings from sub-chronic to chronic toxicity testing (genotoxicity, reproductive toxicity, and organ toxicity). In addition, communication between industry and regulatory authorities will be formulated early in order to allow the most optimal scientific approach. 

The guidelines developed by IPEC-Americas provide for a tier approach to required testing. The tests to be conducted are based upon the route of application of the formulated drug and the duration of use. A base set of data is required for all candidate excipients. The guidelines require a review of the chemical and physical properties of the excipient and a review of the scientific literature, exposure conditions (including dose, duration, frequency, route, and user population), and absence or presence of pharmacological activity. 

Worth AP. The tiered approach to toxicity assessment based on the integrated use of alternative (non-animal) tests. In Cronin MTD, Livingstone DJ, editors, Predicting chemical toxicity and fate. Boca Raton, FL CRC Press, 2004. p. 391 412. 

The third mandated test according to ISO 10993-1 is Irritation. Irritation is defined as a localized inflammatory response to single repeated, or continuous applications of the test substance without involvement of an immunological mechanism. ISO 10993-10 purposes a four-tier approach to assessing the potential of a material to cause irritation. A device manufacturer should first conduct a review of the literature to determine whether others have reported that the chemical or material under consideration, or structurally related chemicals or materials, can cause irritation. It is essential that the chemical or material of interest already be sufficiently characterized that it can be correlated to those described in the literature. The second step is to use available, validated in vitro tests (such as cytotoxicity assays using mammalian cells in culture) to identify, whenever possible, severely irritating materials without using test animals. 

Induced models are often used to the study the pathogenesis of, and therapeutic venues for relevant autoimmune diseases. Some of these models, in particular EAE and AA models, have also been proposed as means to evaluate the immunomodulatory effects of chemicals on established autoimmune diseases in the Tiered Approach of immunotoxicity testing. 

If animal testing is required, a full-scale Draize test may not be necessary given the background established in the beginning of the tier approach. For instance, the compound could be tested in a single sentinel animal to obtain confirmation of in vitro data. In addition, other modifications could be used, such as the administration of appropriate anesthetics to the test animals, or the use of the low-volume Draize modification (Falahee et al., 1982 Freeberg et al., 1984 Griffith, 1987). 

The front end of this tier approach is a screen, the functional observation battery (FOB) Gad (1982) or Irwin (1968) screen. This is the tool of choice for initial (and for most of the compounds covered by this volume, the only screen tests for) identification of potentially neurotoxic chemicals. The use of such screens, other behavioural test methods, or what are generally called clinical observations does, however, warrant one major caution or consideration. That is that short-term (within 24 hr of dosing or exposure) observations are insufficient on their own to differentiate between pharmacologic (reversible in the short term) and toxicological (irreversible) effects. 

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