Human studies

Fewer studies have been made with man and they have, of necessity, been confined to the influence of dietary flavonoid supplements on blood and urinary ascorbic acid. A weakness of such studies is that the diet of most subjects contains a substantial amount of flavonoid material — even when obvious sources such as citrus fruits are excluded from the diet. This makes difficult the inclusion of a control group and also reduces the significance of additional flavonoid supplements. Nevertheless, there is some evidence that flavonoids may modify the absorption—retention—stability of ascorbic acid in man. 

Whether the same basic mechanism is accountable for these flavonoid-induced ascorbic acid changes in both the guinea-pig and man is not known. Certainly there can be little doubt that flavonoids may, under specific conditions, influence the tissue concentrations of ascorbic acid in the guinea-pig and probably in man, too. A number of distinct, but not mutually exclusive, explanations have been proferred to account for the apparent enhancement by flavonoids of ascorbic acid status in guinea-pigs. Four of these merit some discussion. 

An apparatus suitable for human breath collection was described by Lemoyne et al. (1987). Subjects were allowed to breathe for 4 min through a mouth piece connected to a Rudolph Valve from a Tedlar bag (Analygas Systems Ltd., Scarborough, Ontario, Canada) containing hydrocarbon-free air. Atmospheric air was hushed from the lungs and an aliquot of exhaled air collected during the succeeding 2 min while the hydrocarbon-free air was inspired. Hydrocarbons were concentrated by a loop-concentrator similar to that previously described and then injected into the GLC. 

A simple method for the analysis of small volumes of gas from single-breath samples from humans was described by Zarling and Clapper (1987). Total breath samples were collected into a gas-tight bag and 50 ml aliquots withdrawn into polyethylene/polypropylene syringes. Alveolar breath samples collected by use of a Haldane-Priestly tube were also collected in this way. Gas samples were injected directly into the GLC via a gas-sampling valve. 

Many different instruments have been used for the measurement of hydrocarbons in exhaled air. They include the Varian Model 6000 (Varian Instrument, Sunnyvale, CA, U.S.A.) (Zarling and Clapper, 1987), Shimadzu 6-AM (Shimadzu, Seiggkuska Ltd., Kyoto, Japan) (Lemoyne et al., 1987) and Hewlett-Packard Model 5750 (Lawrence and Cohen, 1984). Gas samples are injected either directly into a sampling loop (10 ml volume) (Zarling and Clapper, 1987) or via stainless steel loops (0.2 cm i.d. x 23.4 cm) packed with adsorbents such as activated alumina (80-100 mesh) (Lemoyne et al., 1987) in order to concentrate the alkanes in the sample. 

Concomitant measurement of alkanes in exhaled air may be achieved using a 2 metre Chromosorb 102 stainless-steel column (Varian Associates) with a carrier gas flow of 30 ml/min, an injector tern- 

Occupational or environmental cadmium exposure has been associated in some studies with development of cancers of the lung, prostate, kidney, liver, hematopoietic system, and stomach (Kipling and Waterhouse 1967  

Berg and Burbank 1972 Kolonel 1976 Lemen et al. 1976 Bako et al. 1982 Thun et al. 1985 Blinder et al. 1985 Kazantzis 1987 Kazantzis et al. 1988 Abd Elghany et al. 1990 Campbell et al. 1990 Stayner et al. 1992). The evidence is presently considered clear enough to establish a linkage between cadmium exposure and human neoplasia, at least within the lung (Stayner et al. 1992) however, in other tissues the association is controversial (prostate) or preliminary (kidney, liver, stomach, hematopoietic system) until additional confirmatory evidence is available. 

A theoretical description of critical windows during this interval has recently been described (Morford et al., 2004). The periconception critical window is unique in that it is consistent with the couple-dependent nature of human reproduction and the potential for maternal, paternal, and/or parental exposures (Chapin et al., 

Once exposures are identified and measured, it is necessary to determine how best to measure growth and development. If pregnant women comprise the study population, repeated fetal measurements will be needed at standardized intervals. Growth requires a 

Unlike adults (Hutchinson et al., 1992), there is no universally accepted methodology for measuring infant and child development in relation to environmental exposures. The selected approach must be age, gender, and culturally appropriate. A number of evaluation tools exist for measuring targeted aspects of infant or child development, especially motor, cognitive, or sensory domains. Many instruments can be jointly administered to ensure assessment of various aspects of development. 

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The biological activity of various vitamin E forms was estabUshed by the fetal resorption assay ia tats and is assumed to be appHcable to humans. The results of some human studies may iadicate that the ratio of 1.36 underestimates the biological activity of the RRR form relative to the all-rac form of a-tocopheryl acetate (10—12). 

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

Piaacidil has a short half-life and most human studies were carried out ia slow-release formulatioas. The reductioa ia blood pressure produced by piaacidil is accompanied by tachycardia and fluid retention. Plasma catecholamines and renin activity are iacreased. Other side effects are headache, di22iaess, and asthenia. 

In the first step of the evaluation, the available data are evaluated to determine the likelihood that the agent is a human carcinogen. The evidence is characterized separately for human studies and animal studies as sufficient. 

If no adequate human studies have been done, animal studies are negative. 

Human studies are lacking, and animal studies are either positive for fetal risk or lacking. 

The primary objective of a Phase I trial is to assess the safety of the drug in humans. Studies are normally conducted in healthy male volunteers, although specific categories of subject may be used in certain cases. For example, to avoid the risk of low blood pressure, subjects with mild hypertension would be more appropriate for the evaluation of antihypertensive drugs, while patients are likely to be used in the case of drugs that are expected to produce significant toxic effects (e.g. anti-cancer cytotoxic drugs). Remuneration may be offered for participation in the study. The number of subjects is normally between 10 and 100 people. 

Reports of Bioanalytical and Analytical Methods for Human Studies... 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-efifect level (NOAEL-from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. 

Experimental animals exposed to sublethal doses of cyclodienes show a similar picture, with changes in EEG patterns, disorientation, loss of muscular coordination and vomiting, as well as convulsions, the latter becoming more severe with increasing doses (Hayes and Laws 1991). It is clear from these wide-ranging studies that a number of neurotoxic effects can be caused by cyclodienes at levels well below those that are lethal. In the human studies described here, subclinical symptoms were frequently reported when dieldrin blood levels were in the range 50-100 pg/L, an order of magnitude below those associated with lethal intoxication. 

Peroxidation of lipids is another factor which must be considered in the safety evaluation of liposome administration. Smith and coworkers (1983) demonstrated that lipid peroxides can play an important role in liver toxicity. Allen et al. (1984) showed that liposomes protected by an antioxidant caused less MPS impairment than liposomes subjected to mild oxidizing conditions. From the study of Kunimoto et al. (1981) it can be concluded that the level of peroxidation in freshly prepared liposome preparations and those on storage strongly depends both on the phospholipid fatty acid composition and on the head group of the phospholipid. Addition of appropriate antioxidants to liposomes composed of lipids which are liable to peroxidation and designed for use in human studies is therefore necessary. 

A NOAEL (humans) study that produced a tumorigenic response... 

Human studies have reported hepatorenal failure as the cause of death following accidental ingestion of trichloroethylene (Kleinfeld and Tabershaw 1954 Secchi et al. 1968). It was not possible to determine an accurate dose in these cases. 

Following dermal exposure, trichloroethylene has been detected in blood and expired breath in human studies (Sato and Nakajima 1978). Studies of distribution among other tissues after dermal exposure in humans and animals were not located in the available literature. 

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