Human Test Examples

Use of in vivo Tests. In vivo tests are more relevant indicators than are in vitro tests of immunotoxicity since the dynamic interactions between the various immuno-components, as well as the pertinent pharmacokinetic (absorption, distribution, plasma concentrations) and metabolic factors, are taken into consideration. However, it is important to select the appropriate animal model and to design the protocol such that it will accurately reflect drug (or relevant metabolite) exposure to humans. For example, one should consider species variability when selecting the animal model, since biological diversity may further obscure the ability to accurately predict human toxicity. 

TABLE 13.2 Types and examples of translational, humanized test models... 

Twenty-seven out of 44 FDA-approved biopharmaceuticals have been tested in a battery of genotoxicity assays. Eighty-five different assays performed yielded negative results. The most commonly performed assays were the Ames test, the chromosomal aberration assay in human lymphocytes, the mouse lymphoma gene mutation assay, and the mammalian in vivo erythrocyte micronucleus test. Examples of the range of biopharmaceutical products tested include, domase alfa (deoxyribonuclease I-DNAse), trastuzumab (mAb to human epidermal growth factor receptor 2), alteplase (tissue plasminogen activator), infliximab (mAb to the human tumor necrosis factor a). 

Many of the same issues raised with respect to experimental animal studies also apply to human testing and to the choices of particular tests to be utilized. There are numerous tests that can be utilized for measurement of behavioral functions in humans, and questions remain as to the correct choice. One consideration related to the various tests is deemed validity and refers to the degree to which the test actually measures the behavioral function that it was designed to measure. For example, does a test of memory really evaluate memory function In addition, how specifically does the test measure that function The related issue was raised in experimental animal studies in which the possibility that changes in motor, sensory, motivational processes, etc. might contaminate a measure of memory function, and appropriate controls were included in the more advanced procedures to evaluate those possibilities. 

Human safety evaluations begin with the specific ingredients, and then move on to the whole product. The effects for all ingredients are considered as the product is formulated. Human safety-related data for a chemical used in a detergent or soap product (or in another type of consumer product), and for an entire formulation, can come from in silico data (from computer programs that estimate toxic properties based on data for similar chemicals, and/or from the physical chemical properties of the chemical of interest), in vitro data (from the results of alternatives to animal tests, e.g., from cell cultures used to assess eye or skin irritation potential), animal (toxicological) studies (e.g., to assess eye or skin irritation potential), and human data (examples are discussed below). 

E = Efficacy topics, that is, those relating to clinical studies in human subject. Examples E4 Dose-Response Studies, Carcinogenicity Testing, E6 Good Clinical Practices. 

Whiten Thinking about this issue the other way round, would it help to satisfy Nick Mackintosh s concern about comparability if you did the same tests in other species, particularly primates, including humans For example, you could put children in similar testing situations and compare their responses with conventional IQ test results. 

After the antibodies have demonstrated acceptable sensitivity, one should proceed to testing for specificity (cross-reactivity) with structurally similar compounds or compounds that are most likely to be present in the assay matrix. The assay specificity was determined by running the cotinine assay in the presence of compounds structurally similar to cotinine or likely to be present in human samples. Examples included caffeine, nicotinic acid, nicotinamide, and aspirin. Protocol (Number 4) provides testing for assay specificity with the following steps ... 

There was extensive human testing, often involving scores of men at a time. Some of the tests were so drastic, one wonders what could possibly have motivated men to go through with them. In 1922, for example, twenty observers were placed in a gas chamber for ten minutes exposure ( the limit of tolerability ) to the arsenic gas DA and suffered... 

Of all the short-term assays, the Ames Salmonella test is clearly the best validated and most widely used and will continue to be so for a number of years to come. The assay has an excellent record for identifying organic carcinogens, particularly carcinogens which are in the aromatic amine and polycyclic hydrocarbon classes. " In addition, positive results in the Ames assay and several other short-term mutagenesis assays, have been predictive of carcinogenic activity in rodent assays for a number of compounds with widespread human exposure. Examples of these include the food preservative furylfuramide AF-2 which was used extensively in Japan from 1965 to about 1977 the flame-retardant tris-B-P (tris[2,3-dibromopropyl]phosphate) which was used to treat children s sleepwear from 1972 to 1977 and aromatic amine components of hair dye preparations. 

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