Studies in Humans

No long-term studies of the chronic health effects, including cancer, of JP-8 exposure have been conducted. With regard to epidemiologic studies of related jet fuels, one additional study published after the release of the 1996 NRC report was identified (Parent et al. 2000). Numerous studies of the carcinogenic potential of gasoline streams and related middle distillates have appeared in the open literature. 

The subcommittee is aware of a suspected cancer cluster in Fallon, Nevada, and that exposure to JP-8, originating from a naval base located in that town, is under investigation as a possible cause of the cluster (exposures to other chemicals are being investigated as well). Since 1997, sixteen persons currently or previously living in Fallon have been diagnosed with acute lymphocytic leukemia (ALL), a type of childhood cancer. One case of ALL would be expected approximately every 5 yr in Churchill County, where Fallon is located, based on the size of the population (Nevada State Flealth Division 2002). No scientific studies were found that examined a potential relationship between ALL and JP-8 exposure therefore, the subcommittee could not reach any conclusion concerning exposure to JP-8 and this suspected cancer cluster. 

---

An hplc assay was developed suitable for the analysis of enantiomers of ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory dmg (NSAID), in plasma and urine (59). Following the addition of racemic fenprofen as internal standard (IS), plasma containing the KT enantiomers and IS was extracted by Hquid-Hquid extraction at an acidic pH. After evaporation of the organic layer, the dmg and IS were reconstituted in the mobile phase and injected onto the hplc column. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (chiral AD) with hexane—isopropyl alcohol—trifluoroacetic acid (80 19.9 0.1) as the mobile phase pumped at 1.0 mL/min. The enantiomers of KT were quantified by uv detection with the wavelength set at 254 nm. The assay allows direct quantitation of KT enantiomers in clinical studies in human plasma and urine after adrninistration of therapeutic doses. 

In vitro studies in human liver fractions indicated that azacitidine may be metabolized by the liver. Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 

Efficacy (E) dealing tvith clinical studies in human subjects. 

On the other hand, clinical and laboratory studies in humans have demonstrated the development of tolerance to the amnestic and analgesic effects of nitrous oxide and isoflurane (see Arnold et al. 1993 Avramov et al. 1990 Rupreht et al. 1985 Whitwam et al. 1976) and, in the case of ether or chloroform, to its reinforcing effects (Krenz et al. 2003). No studies have shown the development of tolerance to the reinforcing effects of nitrous oxide. 

Despite the paucity of systematic studies in humans, the available evidence suggests that, like drugs such as alcohol, sedatives, and stimulants, inhalant drugs (i.e., solvents, general anesthetics, and nitrites) exert reinforcing effects and increase motor activity. Furthermore, with continuous use, these drugs appear to induce both tolerance and symptoms of withdrawal. 

A third aspect concerns heat loss mechanisms. Most animals lose heat either by sweating or by panting. Doubly labeled water studies in humans (Schoeller 1988 Wong et al. 1988) indicate that respiratory waters (mouth and nasal) have 5 0 values that can be 10%o to 20%o lower than sweat. Thus, animals that pant could be expected to increase their body water 5 0 compared to animals that sweat. 

Stable isotope studies in human evolution. Evolutionary Anthropology 4 83—98. 

Several studies in animals suggest that age may affect susceptibility to methyl parathion toxicity, and that children may be more susceptible than adults, but the data are limited. (See Section 3.7 for more information on Children s susceptibility.) A study in humans showed that mean erythrocyte acetylcholinesterase activity levels increase with increasing age from birth through old age in both sexes (Garcia-Lopez ad Monteoliva 1988), but it is not known whether increased erythrocyte acetylcholinesterase activity indicates decreased susceptibility to methyl parathion. 

Toxicology studies must be performed in at least two animal species. If the toxicity profile of the compound is acceptable, then it joins the hit or lead list of compounds to proceed. The metabolism of the compound must be understood and pharmacokinetic studies must be performed in small and large animals. Efficacy studies must be performed in relevant animal models, especially in chimpanzees when more than one candidate is identified and a choice has to be made before proceeding to studies in humans. The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others. 

Renal Effects. Triehloroethylene may have effeets in the kidney however, studies in humans are limited by having poor or no exposure data and by concomitant exposure to other chemicals. There was no evidence of kidney damage in 250 neurosurgery patients who underwent prolonged trichloroethylene anesthesia (Brittain 1948), nor in 405 women who had caesarean sections and were exposed to trichloroethylene anesthesia (Crawford and Davies 1975). 

Following inhalation exposure to trichloroethylene in humans, the unmetabolized parent compound is exhaled, whereas its metabolites are primarily eliminated in the urine. Excretion of trichloroethylene in the bile apparently represents a minor pathway of elimination. Balance studies in humans have shown that following single or sequential daily exposures of 50-380 ppm trichloroethylene, 11% and 2% of the dose was eliminated unchanged and as trichloroethanol, respectively, in the lungs 58% was eliminated as urinary metabolites and approximately 30% was unaccounted for (Monster et al. 1976, 1979). Exhaled air contained notable concentrations of trichloroethylene 18 hours after exposure ended because of the relatively long half-life for elimination of trichloroethylene from the adipose tissue (i.e., 3.5-5 hours) compared to other tissues (Fernandez et al. 1977 Monster et al. 1979). 

With the exception of studies examining reproductive outcome in people exposed to trichloroethylene in drinking water (ATSDR 1997 MDPH 1994), intermediate-duration studies in humans following oral exposure were not available. Intermediate-duration oral studies of trichloroethylene in animals (Barret et al. 1991, 1992 Buben and O Flaherty 1985 Constan et al. 1995 Dawson et al. 1993 Goel et al. 1992 Isaacson et al. 1990 Mason et al. 1984 Merrick et al. 1989 NCI 1976 NTP 1988, 1990 Stott et al. 1982 Tucker et al. 1982 Zenick et al. 1984) are available, but did not adequately provide exposure levels that could be... 

Group A5 Not suspected as a human carcinogen. Trichloroethylene is not suspected to be a human carcinogen on the basis of properly conducted epidemiologic studies in humans. 

Classically, to measure absolute absorption the plasma area imder the curve from an intravenous dose would be compared to that caused by the feeding of an oral dose. However, the carotenoids are lipid-soluble and are normally incorporated in chylomicrons synthesised in the enterocytes, a situation that cannot be replicated and applied to studies in humans because an intravenous preparation that would behave naturally is not possible. 

Rice bran fiber has fructo-oligosaccharides - a pre-biotic that helps friendly bacteria to proliferate in the gastrointestinal environment and improves intestinal and colon health (Tomlin and Read, 1988). Recent studies in humans (Kahlon and Chow, 1997) have revealed that rice bran fiber not only normalizes bowel function, but also helps in conditions such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and Crohn s disease, and lowers the lipid levels. Rice bran fiber has been shown to significantly reduce renal stones (Jahnen et al., 1992). It is a good source of fiber in weight loss programs and therapeutic fiber diets for diabetics and heart patients. Fiber diets prevent cancer of the colon and large bowel, control obesity and improve bowel function. 

The degree of confidence in the final estimation of risk depends on variability, uncertainty, and assumptions identified in all previous steps. The nature of the information available for risk characterization and the associated uncertainties can vary widely, and no single approach is suitable for all hazard and exposure scenarios. In cases in which risk characterization is concluded before human exposure occurs, for example, with food additives that require prior approval, both hazard identification and hazard characterization are largely dependent on animal experiments. And exposure is a theoretical estimate based on predicted uses or residue levels. In contrast, in cases of prior human exposure, hazard identification and hazard characterization may be based on studies in humans and exposure assessment can be based on real-life, actual intake measurements. The influence of estimates and assumptions can be evaluated by using sensitivity and uncertainty analyses. - Risk assessment procedures differ in a range of possible options from relatively unso-... 

There are no studies in humans directly demonstrating increased production of ROM in alcoholic liver disease. However, indirect evidence does support the hypothesis that ROM are involved in the pathogenesis of ethanolic liver injury (Arthur, 1988 Tsukamoto et al., 1990 Nordmann et /., 1992). Basal whole blood... 

Effects In Humans. Neither postmortem nor functional cerebrospinal fluid (CSF) studies in humans provide firm evidence for similar, long-term damages or alterations to monoaminergic neurons in chronic stimulant abusers. In part, the lack of demonstrable neurochemical changes may well be due to the obvious preclusion of well-controlled prospective experimentation in humans, as well as to variability in critical variables (e.g., individual sensitivity or pattern of abuse) encountered in clinical research. Possible relationship of the various complications of stimulant abuse including hyperpyrexia, seizure, anoxia, and metabolic exhaustion to neuronal chromatolysis, terminal destruction, and monoamine and enzymatic depletion have not been systematically explored in human autopsy eases. It should be also noted that, under nonperturbed conditions, overt behavioral deficits are rare in... 

Griffiths, R. R., and Woodson, P. P., Reinforcing properties of caffeine studies in humans and laboratory animals. Pharmacol. Blochem. Behav. 1987. 

Of ultimate importance are the full reports of the clinical studies in humans and their results. These data will be treated statistically for their validity. The number of studies for a specific compound or combination of compounds will vary with the type of drug being tested, as will the number of tests needed to appraise relative or absolute safety and to clearly demonstrate efficacy. The basic requirement is the proof of safety and efficacy of the product being submitted under the NDA system. A drug that does not contribute to therapy, such as a new antihistamine that does not demonstrate greater safety or efficacy, or both, compared with drugs already on the market, will have a difficult or impossible time achieving approval. 

---