Studies on Humans

When the data as a whole are reviewed for studies on humans exposed to ethylene oxide, no conclusion can be made that there is an increase in mortahty associated with those exposed to ethylene oxide. Two Swedish studies (247,248) indicated an increase in leukemia for workers exposed to multiple chemicals including ethylene oxide however, in a recent larger Swedish study (249) of workers exposed to only ethylene oxide, there was no association of any type of cancer increase for these workers. In a recent study sponsored by NIOSH, there was no significant increase in mortahty observed for cancer when all types are combined or for certain individual types of cancer, even for those people who worked the longest and were observed the longest. However, a statistically significant increase in mortahty from certain types of lymphoma was observed for male workers. This is contrary to the results observed for female workers. In addition, four other cohort studies of ethylene oxide-exposed workers have been pubhshed (250—253), but no unequivocal increase in the risk of cancer was observed. 

Borkowski, R. J. et al., 1984, In-Plant Reliability Data Bank for Nuclear Plant Components a Feasibility Study on Human Error Information, ORNL/TM 9066, March. 

Reimer, A., von Mecklenberg, C., and Toremalm, N. G. (1978). The mucociliary activity of the upper respiratory tract. III. A functional and morphological study on human and animal mare-tial with special reference to maxillary sinus diseases. Acta Otolaryngol., 1-20. 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

Knockout mice have been reported for several FATPs [1]. As insulin desensitization has been closely linked to excessive fatty acid uptake and intracellular diacylgly-cerol and TG accumulation, these animal models were particularly evaluated in the context of protection from diet-induced type 2 diabetes ( Type 2 Diabetes Mellitus (T2DM)). In addition, studies on human subjects have also established genetic links between polymorphisms in FATP genes and metabolic alterations [1]. 

Mori K, Nagasawa S Studies on human high molecular weight (HMW) kininogen. If. Structural change SS of HMW kininogen by the action of human plasma kallikrein. J Biochem 1981 89 1465-1473. 

Calculated molecular descriptors including H-bond parameters were used for QSAR studies on different types of permeabiUty. For example, the new H-bond descriptor characterizing the total H-bond ability of a compound, was successfully appUed to model Caco-2 cell permeability of 17 drugs [30]. A similar study on human jejunal in vivo permeabiUty of 22 structurally diverse compounds is described in Ref. [62]. An exceUent one-parameter correlation of human red ceU basal permeabiUty (BP) was obtained using the H-bond donor strength [63] ... 

Birke G, Johnels AG, Plantin LO, Sjostrand B, Skerfving S, Westermark T. 1972. Studies on humans exposed to methyl mercury through fish consumption. Arch Environ Health 25 77-91. 

Schmidt, H. L. (1986). Food quality control and studies on human nutrition by mass spectro-metric and nuclear magnetic resonance isotope ratio determination. Fresenius Z. Anal. Chem. 324, 760-766. 

Robert A. Kehoe. His lead studies on humans include the following, arranged chronologically ... 

The health effect side of the diagram shows that unit risk estimates result from interactive analyses of health-affecting processes in the human body and observed effects in human populations (epidemiology). Health effects are identified by integrating clinical studies on humans or animals with studies of physical and chemical responses to pollutant agents in the human body. 

The main pre-clinical species used for pharmacokinetic studies are the rat, mouse and dog. An examination of the Biosys database for 2000 and 2001 shows that of the abstracted papers, 6334 mapped to the subject heading Pharmacokinetics . Of these, the vast majority (70%) were studies on humans. Studies on rats constituted 14% of the reports, mice 7.5% and dogs 3.4% (Table 6.2). Nonhuman primates can also be important pharmacokinetic models, but ethical and practical considerations severely limit studies in these animals such that, within the same period, they represented less than 0.5% of the abstracted reports on PK. 

The scientific data on the effects of tamoxifen on uterine leiomyomas are generally extrapolated from safety data on the use of tamoxifen in women with breast cancer, and for this reason the studies available are essentially clinical studies on human models. 

Kanaori, K., Nosaka, A., J. Studies on human calcitinin fibrillation by protonnuclear magnetic resonance spectroscopy Characterization of the lyophilized fibril. Proceedings of the International Society of Magnetic Resonance, Xll,h meeting, part 1, p. 274-275. Bull. Magn. Reson., 17, p. I —4, 1995... 

In the studies on humans there appeared to be decreased calcium balances when 200 g or more of spinach per day was included in the diet. In two of the studies in which women were fed spinach, calcium intakes were below the Recommended Dietary Allowance of 800 mg/day (37). Some studies were conducted for short period of a week or less, which may not be sufficient time to adjust to a change in diet. From measurement of calcium excretion in urine after a test meal, it was shown that the calcium in oxalate-containing vegetables was less well-absorbed than that of milk or of vegetables not containing oxalic acid. However, this would not necessarily affect calcium balance, since the total amount of calcium in the diet would have to be considered. The effect of a combination of oxalic acid and fiber on calcium bioavailability should be further investigated. 

Possible sources of semiochemicals in primates include the scalp, hair, axillary region, genitals, chest and/or breast, feet and skin. As possible starting points for studies on human semiochemicals, the constituents present in the effluvia, excretions and secretions of humans have been characterized. For example, a large number of constituents of normal human urine have been identified since modern gas chromatographic techniques became available for this type of analysis. The results of these earlier studies on human effluvia and urine have been reviewed by Albone [148]. 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

Cui, J.-F., Bjorkhem, 1., and Eneroth, P. (1997). Gas chromatographic-mass spectrometric determination of 20(S)-protopanaxadiol and 20(S)-protopanaxatriol for study on human urinary excretion of ginsenosides after ingestion of ginseng preparations. /. Chromatogr. B 689, 349-355. 

Several studies on human musculature have been performed using C... 

Convincing new information on the health effects of oxidant exposure has emerged from controlled studies on humans, from which tentative dose-response curves have been constructed. These data are reviewed in Chapter 9, with the types of experimental facilities now available for such measurements. The new data show reduced pulmonary function in healthy smokers and nonsmokers after exposure to ozone at 0.37 ppm and higher for 2 h. The federal standard is 0.08 ppm for a I-h exposure.) Other gases and aerosols found in an urban atmosphere were not present in these experiments. 

Hackney, J. D., W. S. Unn, D. C. Uw. S. K. Karuza, H. Greenberg, R. D. Buckley, and E. E. Pedersen. Experimental studies on human health effects of air pollutants. III. Two-hour exposure to ozone alone and in combiiuition with other pollutant gases. Arch. Environ. Health 30 385-390, 1975. 

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