Experimental animal studies

Experimental animal studies have played a key role in the understanding of the mechanisms of chemical carcinogenesis. The duration of development of a cancer in humans may be several decades, and the development probably includes several steps. Furthermore, individual susceptibility is also important for the disease. Therefore, it has been extremely difficult to make the required observations in exposed individuals. 

Comparative Toxicokinetics. In humans, the targets for trichloroethylene toxicity are the liver, kidney, cardiovascular system, and nervous system. Experimental animal studies support this conclusion, although the susceptibilities of some targets, such as the liver, appear to differ between rats and mice. The fact that these two species could exhibit such different effects allows us to question which species is an appropriate model for humans. A similar situation occurred in the cancer studies, where results in rats and mice had different outcomes. The critical issue appears to be differences in metabolism of trichloroethylene across species (Andersen et al. 1980 Buben and O Flaherty 1985 Filser and Bolt 1979 Prout et al. 1985 Stott et al. 1982). Further studies relating the metabolism of humans to those of rats and mice are needed to confirm the basis for differences in species and sex susceptibility to trichloroethylene s toxic effects and in estimating human heath effects from animal data. Development and validation of PBPK models is one approach to interspecies comparisons of data. 

Immunotoxicology data most often available for use in risk assessment is derived from experimental animal studies. Although animal models provide an opportunity to establish more reliable exposure estimates and conduct more informative tests than human studies, the level of accuracy that can be achieved using such data in extrapolating to humans is often a matter of debate. In immunotoxicology testing, a set of tests usually referred to... 

The gold standard for human studies is called the randomized, controlled clinical trial. Such trials are close to experimental animal studies, but for obvious ethical reasons, they cannot be conducted to identify toxicity. They are, instead, designed to determine whether certain pharmaceutical or nutritional regimens, for example, reduce the risks of disease. They may provide information about adverse side effects, but they are not designed for studying toxicity. 

Extrapolation of data from studies in experimental animals to the human situation involves two steps a first step is to adjust the dose levels applied in the experimental animal studies to human equivalent dose levels, i.e., a correction for differences in body size between laboratory animals and humans. A second step involves the application of an assessment factor to compensate for uncertainties inherent in toxicity data as well as the mterspecies variation in biological susceptibility. These two steps are addressed in the following sections. 

Eor the observed dose in an experimental animal study, and the equivalent dose in man,... 

When the observed dose in an experimental animal study is expressed in mg/kg body weight, then the equivalent human dose (in mg/kg body weight) is equal to the dose in the experimental animal study divided by a scaling factor according to the following equation ... 

Consumers and workers may be exposed to a variety of chemicals via different exposure routes. This exposure can be judged to be acute, subchronic, or chronic by analogy with the exposure schedules in the various experimental animal studies. The spatial scale of exposure is at the personal level. At the risk characterization step, the actual or estimated acute, subchronic, and chronic exposure level can be compared with a suitable DNEL derived from the acute, subchronic, and chronic studies, respectively. 

Toxicology. Amitrole has low acute toxicity in experimental animal studies subchronic exposures were associated with changes in the thyroid and chronic exposures were carcinogenic. 

Nephropathy has been associated with chronic lead poisoning. " A study of two large cohorts of heavily exposed lead workers followed through 1980 demonstrated a nearly threefold excess of deaths attributed to chronic nephritis or other hypertensive disease, primarily kidney disease. Most of the excess deaths occurred before 1970, among men who began work before 1946, suggesting that current lower levels of exposure may reduce the risk. Experimental animal studies suggest there may be a threshold for lead nephrotoxicity, and in workers, nephropathy occurred only in those with blood levels over 62p,g/dl for up to 12 years."... 

The fat-soluble vitamins comprise vitamins A, D, E, and K, whose biological activities are attributed to a number of structurally related compounds known as vitamers. Also included are those carotenoids that are precursors of vitamin A. Recommended dietary allowances (RDAs) based on human epidemiological and experimental animal studies have been published in the United States for vitamins A, D, E, and K (1). Other countries and international bodies have compiled similar recommendations. In the United States and Canada, fluid milk is supplemented by law with vitamin D to a level of 400 international units per quart (10 /zg/0.95 L) to meet the RDA of 10 p%. Other commodities, such as margarine, milk products, ready-to-eat breakfast cereals, and dietetic foods, are commonly supplemented with vitamins A, D, and E. Except for infant formulas, vitamin K is not added to foods. The addition of vitamins to a particular processed food is intended to provide a specific proportion of the RDA. 

Epidemiological studies showed positive association of coffee drinking and cancers of pancreas and ovary (18,19,20), although reports describing negative association are also available (21,22). In an experimental animal study, no carcinogenic activity of coffee was reported (46,47). However, this data should be reconsidered in terms of the genotoxic activities of coffee revealed in bacteria and cultured mammalian cells. 

In general, the adverse effects of radium are believed to be the consequence of the radiation emitted from the element itself and its daughter products. Because there is already a considerable amount of information on the effects of radiation on humans and animals derived from studies on the effects of the atomic bomb and of therapeutic x-ray and gamma-ray treatments of malignancies, the experimental animal studies with radium have made no attempt to duplicate this information. They have instead concentrated on radium s most sensitive endpoint, cancer. For example, it can be predicted that the beta and gamma rays emitted by a radium source will produce local radiation burns and tissue damage when the source is placed on human or animal skin, hence there have been no valid reasons to conduct such studies with radium. 

There is little in the literature relative to vitamin A and colon cancer in human populations. Experimental animal studies, however, strongly suggest that vitamin A deficiency may have a role in this type of cancer. We have shown that a deficiency of vitamin A increased DMH-induced tumors and shortened the lag time for induction, compared to normally supplemented controls (72). More recently (73) we have confirmed a protective role for vitamin A in colon carcinogenesis (Table XVII). Furthermore, we have shown (74) that vitamin A deficiency can result in colon tumors in rats given aflatoxin (AFB ) which is normally a liver carcinogen (Table XVIII). The colon tumors associated with the hepatocarcinogen AFB.. appear to be a result of differences in metabolism and binding of AFB or its metabolite ) to colon DNA under conditions of vitamin A deficiency (75). 

In parenteral therapy, the subcutaneously implantable, osmotic mini-pumps developed by the Alza Corp. are used widely in experimental animal studies. The DUROS implant pump is a modified version of the Alzet pumps and was developed specifically for the controlled delivery of peptides and proteins (see Section 4.6.1.2). Osmotic mini-pumps, such as the Oros osmotic pump, are also available for controlled... 

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