Studies in Volunteers

When they are already available, well-conducted human exposure smdies in volunteers can be used in the hazard assessment. Studies in human volunteers are experimental studies in which the subjects, often young and healthy persons, are exposed to known, generally low doses or concentrations of a substance for a well-defined, generally short exposure period. 

As studies in human volunteers are performed under standardized conditions with well-defined exposure concentrations or doses, but only for a short duration, such studies are most relevant for hazard assessment of mild acute effects, mild irritation, sensitization, toxicokinetics, and mode of action(s). 

Over the years, scientific research with human subjects has provided valuable information to help characterize and control risks to public health, but its use has also raised particular ethical concerns for the welfare of the human participants in such research as well as scientific issues related to the role of such research in assessing risks. Society has responded to these concerns by defining general standards for conducting human research. As an example, studies carried out for the authorization of a medical product, have to be conducted in line with the World Medical Association s Declaration of Helsinki, which describes the general ethical principles for medical research involving human subjects (World Medical Association 2004). The Helsinki Declaration was first issued by the World Medical Association in 1964 and has been revised several times since then. 

Toxicological Risk Assessments of Chemicals A Practical Guide 

Human research issues affect all programs in US-EPA. In its Office of Research and Development, US-EPA conducts research with human subjects to provide critical information on environmental risks, exposures, and effects in humans. This is referred to as first-party research. In both its Office of Research and Development and its program offices (including the Office of Air and Radiation, the Office of Water, the Office of Solid Waste and Emergency Response, and the Office of Prevention, Pesticides and Toxic Substances), US-EPA also supports research with human subjects conducted by others. This is referred to as second-party research. In aU this work US-EPA is committed to full compliance with the common rule. The US-EPA will continue to conduct and support such research, and to consider and rely on its results in US-EPA assessments and decisions. 

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Another unanswered question is the evaluation of the effect on cardiac repolarization of oncologic drugs, for which the thorough QT/QTc study in volunteers cannot be performed [166], In these cases, not only central tendency (i.e. mean QTc increase) and proportion of outliers but also other findings such as syncope, ventricular tachyarrhythmias and other cardiac effects should be more closely defined. 

No quantitative data were located on the absorption of 3,3 -dichlorobenzidine following oral exposure in humans. However, a study in volunteers found acetylated metabolites in the urine 24 hours after a single 250 mg oral dose of 3,3 -dichlorobenzidine, which suggested that the compound is absorbed (Belman et al. 1968). 

Human data include information from case reports (e.g., poisonings), clinical examinations, experimental studies in volunteers, experiences from the working environment, epidemiological studies, and meta-analyses. 

Inorganic arsenic is eliminated primarily via the kidneys in humans as well as laboratory animals. Studies in adult human males voluntarily ingesting a known amount of either As(III) or As(V) indicate that 45-75 % of the dose is excreted in the urine within a few days to a week (Pomroy et al., 1980 Tam, Char-bonneau and Bryce, 1979 Buchet, Lauwerys and Roels, 1981a Buchet, Lauwerys and Roels, 1981b Lee, 1999). Relatively few studies in volunteers have included the measurement of arsenic in both feces and urine. However, Pomroy et al. (1980) reported that 6% of a single oral dose of arsenic acid was excreted in the feces over a period of seven days compared to 62 % of the dose excreted in urine. No quantitative data are available that directly assess the significance of biliary excretion of As(III) or As(V) in humans. 

GRAPEFRUIT JUICE CISAPRIDE T plasma concentrations and likely T risk of adverse effects (e.g. cardiotoxicity, Q-T prolongation, torsade de pointes) t oral bioavailability and slight but significant t elimination half-life Although a study in volunteers did not show any changes in heart rate, PR or Q-T prolongation, avoid concurrent use... 

In the features thus far described, BZ is a typical glycolate, indistinguishable qualitatively from atropine, scopolamine, EA 3834, EA 3443, EA 3580, EA 302,196, or any ocher compounds of the 21 in this family studied in volunteers. 

The ability of the gastroduodenal mucosa to adapt to repeated exposure to NSAIDs and aspirin is well documented, and some reports have shown the possible involvement of H. pylori in this process (76,81). In one endoscopic study in volunteers, mucosal adaptation to naproxen after 4 weeks of treatment occurred in 53% of H. py/on-positive subjects and in 81% in H. py/on-negative subjects (82). 

Similar results were found in another study in volunteers who took aspirin for 2 weeks mucosal adaptation to the injury caused by aspirin was clearly impaired in the presence of H. pylori and was restored after H. pylori eradication (83). 

Treatment begun with streptomycin, gentamicin, doxycycline, or ciprofloxacin during the incubation period and continuing for 14 days may prevent symptomatic infection (43). A small study in volunteers showed that oral tetracycline given within 24h of an aerosol exposure and continued for 14 or 28 days was fully protective, whereas two out of ten volunteers treated for only 5 days developed symptomatic tularemia after stopping treatment. Once pubUc health officials become aware that... 

An IND application must be submitted to the FDA before the first clinical trial in the United States. A regulatory submission may not be required outside of the United States if the study is conducted in volunteers. For IND EIH studies, the project team must plan for the manufacture and release of clinical trial materials as well as for the IND documentation. For a study in volunteers not requiring an IND, documentation needs are reduced but all other activities remain the same. 

Adamantanes. Amantadine hydrochloride (Symmetrel, EXP IO5), now released by the Food and Drug Administration, has been further examined in double-blind studies in volunteers infected with influenza Ag virus nd in epidemics caused by the same virus in adults nd in chll-... 

The drug also has complex cardiovascular and neuroendocrine effecfs, some of which have been studied in volunteers given small "therapeutic" doses under closely controlled conditions. Single doses of MDMA have been shown to significantly increase blood pressure (systolic and diastolic), heart rate, body temperatures... 

Rush, E., Ferguson, L.R., Cumin, M., Thakur, V., Karunasinghe, N., and Plank, L. 2006. Kiwifruit consumption reduces DNA fragility A randomized controlled pilot study in volunteers. Nutr. Res. 26, 197-201. 

Moren J, Francois T, Blanloeil Y, Pinaud M. The effects of a nonsteroidal antiinflammatory drug (ketoprofen) on morphine respiratory depression a double-blind, randomized study in volunteers. Anesth Analg (1997) 85, 400-5. 

Human experience. Human experience is often regarded as the most useful and the most relevant source of information, but does vary considerably in both quality and quantity. For some solvents which have been in use in large quantities for many years, extensive studies of workplace health (known as epidemiology ) may have been carried out. These studies may either have identified adverse effects or have shown the absence of such effects. A shortcoming is often the extent and quality of exposure estimation, absence of which considerably reduces the value of the study. Useful human data may also be available from studies in volunteers exposed to low levels. Individual case reports of adverse effects are of limited value, but may well indicate the need for further more detailed study. 

The prevalence of ILD in RA varies with the mode of detection. ILD is evident on chest radiography in 1% to 6% (139-143). A restrictive defect is infrequent (5-12%), but TLco is reduced in 33% to 57% of unselected patients (31,139,140,144). BAL abnormalities are present in 0% to 33% of patients with no clinical evidence of ILD (140,145-147). In an early SLB study in volunteers with RA, interstitial lesions were disclosed in 60%, without respiratory symptoms in nearly 50% (148). A wide variation in the prevalence of HRCT abnormalities, of 4.2% to 68% (139,140,149-152), probably reflects selection bias. In a study of recent-onset RA, ILD was present on HRCT in 33% (140). However, as HRCT findings correlate poorly with symptoms, chest radiography, and PFT, their clinical relevance is unclear (139,140,149,151,152). In the largest study, ILD was seen on HRCT in 19% of 150 consecutive patients and was associated with bilateral basal crackles in 54%, TLco <75% in 82%, restrictive PFT in 14%, bilateral infiltration on chest radiography in 14%, but dyspnea in only 18% (139). 

Perhaps the major advantage as far as human safety is concerned is that potassium bromide is not very toxic. While it is true that bromism can develop in humans after oral administration, the fact that it takes several months to achieve steady state kinetics means that inadvertent or defiberate ingestion of a dog s medication will not result in toxicity. Studies in volunteers given 1 mg/ kgbw/day (about 60 to 70 mg) for 8 weeks revealed no signs of toxicity. Doses of 4 or 9mg/kgbw/day for 12 weeks to volunteers produced only marginal effects on the thyroid." " ... 

Martin R, Sullivan T, Bhagat L et al (2003) A phase 1 placebo-controlled study in volunteers of escalating doses of HYB2055, a second-generation immunomodulatory agent based on CpG DNA. Presented at the AACR-NCI-EORTC international conference on molecular targets and cancer therapeutics, 17-21 Nov 2003, Boston, MA (abstract ClOO)... 

Viractin, for which there are unconfirmed claims of activity for the prevention of respiratory infection, once again was shown to be ineffective in a cross-over placebo-drug study in volunteers (78). 

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