Studies Using Experimental Animals

Although rats had been used earlier, the introduction of the Syrian hamster as an animal for caries research allowed animal experimentation to become important. The earlier lesions obtained with rats were not typical of human lesions, and factors such as the granule size of foods were of critical importance. More recently, suitable methods of using rats have 

It must be noted, however, that hereditary influences exist, and caries-resistant and caries-susceptible strains of rats have been developed 108). Most dietary compositions used for experimentation have contained sucrose or starch as the principal carbohydrate material. But carbohydrates are not identical in their effects, and both chemical and physical differences may influence their cariogenicity 109). 

---

The biotransformation of a given chemical compound in experimental animals and in humans may differ. Furthermore, high doses of chemical compounds are used in studies with experimental animals, and this may cause alterations in biotransformation of the tested chemicals that do not occur at the lower doses relevant to the human exposure situation. For example, a metabolic pathway dominating at low doses may become saturated, and a salvage metabolic pathway, e.g., one that produces reactive intermediates of the compound, may become involved in the biotransformation of the chemical. Since this intermediate could never be produced at the exposure levels encountered in humans, the overall result... 

Gone are the days when the pharmaceutical scientist could conduct whatever procedures or studies that were desired using experimental animals. The Animal... 

In studies with experimental animals, the reinforcing properties of nicotine seem to be relatively weak and do not appear to be sufficiently powerful to explain the highly addictive nature of tobacco smoke (Donny et al. 2003 Balfour 2004). An early study by Goldberg and colleagues (1981) using squirrel monkeys showed that... 

For most chemical substances, useful and relevant human data are not available. The risk assessment is therefore most often based on studies in experimental animals. The results of animal studies are used to predict the possible effect in humans, i.e., effects in animals are used to model corresponding effects in humans. Animal data are also used as a supplement to human data, which are equivocal, or to identify the active substances in a mixture to which humans have been exposed. 

Finally, the use of different types of information (human data, data from studies in experimental animals, in vitro test data, and other data such as, e.g., data on physico-chemical properties and (Q)SAR) in the hazard assessment for a specific endpoint is addressed in more detail. 

Pharmacokinetic models are used as tools to extrapolate from the results obtained in studies with experimental animals to predict effects in human populations that generally are exposed at lower environmental exposure levels compared to the generally higher exposure levels used in animal experiments. In such models, target tissue doses in different animal species under a variety of exposure conditions are predicted, using computer simulation. 

Today, well over 100 biological parameters of mammals are known to be linearly related to body weight and highly predictable on an mterspecies basis (Davidson et al. 1986, Voisin et al. 1990, Calabrese et al. 1992). The allometric equation has traditionally been used for extrapolation of experimental data concerning physiological and biochemical functions from one mammalian species to another. In addition, the allometric equation has also been used extensively as the basis for extrapolation, or scaling, of e.g., a NOAEL derived for a chemical from studies in experimental animals to an equivalent human NOAEL, i.e., a correction for differences in body size between humans and experimental animals. 

The most frequently used POD for threshold effects (Section 4.2) is the NOAEL (Section 4.2.4). This NOAEL is generally obtained from studies in experimental animals. If reliable human data are available to derive the NOAEL, this value is preferable to the NOAEL from experimental animals. Where a NOAEL cannot be derived, a LOAEL, if available, can be used. An alternative POD to the NOAEL/LOAEL is the benchmark dose (BMD) (Section 4.2.5). The tolerable intake can also, in some cases, form the basis as the POD. In this chapter, the POD will be denoted as a derived no-effect level (DNEL) in order to provide a general term for the various types of PODs that can form the basis for the risk characterization. 

While parenteral exposure is not a route posing a significant environmental threat to human health from the isotopes of radium, data acquired in studies using this route are presented here because thousands of persons did acquire radium via this route, and most of the toxicity and metabolic studies with experimental animals have used this route. It is again important to note that effects observed after parenteral administration of radium may be attributed not only to radium itself, but to the presence of any or all of its daughter products and their radioactive emissions in vivo. 

A Experimental animals to humans Generally use a factor of 10 when extrapolating from results of chronic studies on experimental animals. EPA intends that this factor account for uncertainty involved in extrapolating from laboratory animals to humans. 

In animal studies using experimental white phosphoms burns, there is evidence that phosphoms compounds remaining in the bum site may contribute to the increased mortality. Experimental bums with white phosphoms have resulted in abnormal EKGs in rabbits (Bowen et al. 1971) and extensive renal and hepatic damages in rats (Ben-Hur et al. 1972 Ben-Hur and Appelbaum 1973). Increased mortality in these studies was attributed to the systemic effects of white phosphoms or phosphoms compounds, rather than to the toxicity of the bum. White phosphoms is probably absorbed to a much greater degree from severe burns than from normal dermal exposure. 

Reduced fertility has been found for a number of chemicals, but often at relatively high exposure levels. However, it has to be considered that the rat is the most commonly used experimental animal and that a male rat can generally still produce normal progeny after having its sperm production reduced to 10% of the normal level (Aafjes et al., 1980). Thus, fertility data from rat studies alone can be a rather insensitive end-point. Human males may not have a similar sperm reserve capacity as rodents, and therefore the two-generation study has recently been updated to include assessment of sperm quality. It is unknown whether female rats (compared with human females) are also less sensitive to effects on fertility, but the two-generation study has recently been updated in that aspect by the inclusion of assessment of estrous cyclicity. 

---