Human volunteer testing

Practicalities Associated with Human Volunteer Testing. 507... 

PRACTICALITIES ASSOCIATED WITH HUMAN VOLUNTEER TESTING... 

Many tests can be run on especially designed equipment, but to determine satisfactorily whether there is any CW leakage at the periphery requires human volunteers. Tests were made on all of the races represented in the United... 

Anderson (1944) performed a series of human volunteer tests (six male soldiers per group) using a 100 m chamber, and reported that in humans CK is first detectable by its lachrymator effect between 0.54 and 2.6 mg m . At 17 mg m painful blepharospasm is produced, and concentrations greater than 400 mg m are judged to be immediately intolerable due to respiratory irritation. Based on the results of Anderson, Harrison (1944) concluded that the harassing concentration for offensive purposes may be taken as 20 mg m . ... 

Urinary excretion of radioactivity was measured in human volunteers during and after a 3.5-hour period of dermal exposure to 0.11 or 0.22 g 32P-labeled TOCP (Hodge and Sterner 1943). The specific activity of the test substance was not reported. Radioactivity in urine was measured with a Geiger-Muller counter, but the limits of detection were not reported. Maximum estimated excretion rates, 10 and 43 pg TOCP/hour for the respective dosage levels, were measured within 24 hours of initiation of exposure. Radioactivity was not detected 48 or 72 hours after dosing ceased. Cumulative radioactivity detected in urine accounted for 0.13% and 0.36% of the dermally applied radioactivity. 

In a study by MacEwen et al. (1970) using seven adult human volunteers, 10-min exposure to monomethylhydrazine (90 ppm, or 169 mg/m3) resulted in irritation of the eyes, nose, and throat but did not cause excessive lacrimation or coughing. Clinical chemistry parameters for 60 d following the exposure were not significantly affected a 3-5% increase in Heinz body formation at d 7 declined after 2 w. Additionally, spirometry tests revealed no exposure-related effects. 

Human volunteers exposed to PGDN at various concentrations of also exhibited central nervous system effects (Stewart et al. 1974). At 0.35 ppm, the VER was altered, particularly at 8 h. This effect became more pronounced at 0.5 ppm and 1.5 ppm, after 45-90 min at the latter concentration. After 6.25 h of exposure at 0.5 ppm, two subjects had abnormal heel-to-toe balance tests with their eyes closed, and after 8 h, all three subjects had abnormal modified Romberg tests as well as abnormal heel-to-toe tests with eyes closed. At this time, one subject was unable to perform the heel-to-toe test with open eyes. 

Eight healthy human volunteers, four males and four females, ages 20-24, were exposed individually (whole body) to concentrations at 0 (air), 1,000, 2,000, 4,000, or 8,000 ppm for 1 h in a 13.6 m3 room (Emmen and Hoogendijk 1998 Emmen et al. 2000).2 Each subject was exposed at each concentration in a partially blind ascending order of concentration. With the exception of one 14-d interval, each exposure was separated by a period of 7 d. Chlorofluorocarbon-12 (CFC-12) was used as a reference compound. No mention was made of the ability of the test subjects to recognize the odor of either test chemical. Prior to and during exposures, blood pressure and cardiac rate and rhythm (EKG) were monitored. Pulmonary function, as indi... 

However, the number of studies that can be performed in humans is limited by both ethical (unnecessary exposure of human volunteers to risks) and economical factors. Therefore, in vitro testing may be invoked as a surrogate of the surrogate provided that a linear relationship between relevant in vivo and in vitro exists, i.e., an IVIVC. 

In the first phase of their research, Squibb tested a short-chain peptide isolated from the venom of the viper Bothrops jararaca, with which Vane was working in the laboratory, in human volunteers and showed that it did, indeed, inhibit the conversion of angiotensin I to angiotensin II after intravenous injection. The peptide was also shown to reduce blood pressure in patients when injected. Since the vast majority of peptides cannot be absorbed from the GI tract, Squibb scientists set out to prepare a nonpeptide compound that could be used orally and manufactured at acceptable cost. The design of a true peptidomimetic that became orally active had not been accomplished at that time. Squibb then carried out... 

Although cell lines are often used in preclinical studies, it is also important to test a compound on primary cells from the target tissue itself. Because this tissue must be taken from healthy, human volunteers, such tissue is often difficult to obtain in sufficient quantities for many types of assays that require large numbers of cells. In Figure 7.9, normal peripheral blood mononuclear cells (PBMCs) from four unrelated, healthy donors were treated... 

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