Experimental Studies in Animals

ANTIBACTERIAL PROPERTIES in VIVO Studies in Experimental Animals 

It is understood that nitrofuran derivatives exhibit an outstanding inhibition against various micro-organisms in vitro, although the cure rate of infected animals remains rather low. 

The broth dilution method was used in these studies. Pseudomonas organisms were cultivated in I per cent peptone, 3 per cent NaCi medium, and Dipl, pneumoia. Sir, pyo nes and CoU. Dipktk riae were cultivated on heart infusion broth containing 0 5 per cent glucose. All other bacteria were cultivated on heart infusion broth. F gi were grown in Sabouraud s medium. 

Dodd reported that nitroflirazone was effective against infections with Staph, aureus. Strep, pyogenes, Sal. schottmuelleri, and Sal. typhimurium. It is not effective against Diplococcus pneumoniae. The antibacterial activity of other nitrofurans in vivo is shown in Table 6.25. 

All test compounds are effective against systemic infection with Sal. typhosa. Nitrofurazone, furazolidone, and furaltadone are also effective against infection with Staph, aureus. In 1962 the activity of panfuran in vivo was determined against infections with Strep, pyogenes. Mice were inoculated intraperitoneally with a dose 1,000 times higher than the MLD of bacteria. Thereafter, panfuran and similar compounds were administered subcutaneously at 3, 24, 48, and 72 hours after inoculation. The results prove that panfuran is effective against Strep, pyogenes infections. 

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Studies in experimental animals indicate that both toxic effects and adaptive effects may be seen in the liver following oral exposure to endosulfan. 

Dermal Effects. There have been no reports of adverse dermal effects associated with exposure to endosulfan in humans. When tested in farmers, endosulfan did not cause contact dermatitis (Schuman and Dobson 1985). Studies in experimental animals have shown that dermal exposure to endosulfan is only slightly to moderately irritating at relatively high doses (Hoechst 1983b, 1985c, 1985d, 1989b Industria Prodotti Chimici 1975). 

Balazs, R. (1976). Assessment of the value of systemic toxicity studies in experimental animals. In Advances in Modern Toxicity, Vol. 1 Part 1 New Concepts in Safety Evaluation (Mahlman, M., Shapiro, R. and Blumenthal, H., Eds.). Hemisphere Publishing, Washington, D.C., pp. 141-153. 

No information was located regarding the gastrointestinal toxicity of chlordecone in humans. Only very limited evidence of gastrointestinal effects has been observed in oral studies in experimental animals (Fujimori et al. 1983 Larson et al. 1979b). Thus, it is unlikely that chlordecone exposure would result in adverse effects on the gastrointestinal tracts of persons exposed to low levels at hazardous waste sites. 

Studies in experimental animals suggest that biliary excretion of chemicals from the liver may be impaired by mirex or chlordecone (Berman et al. 1986 Curtis and Hoyt 1984 Curtis and Mehendale 1979 Curtis et al. 1979b, 1981 Davison et al. 1976 Mehendale 1976, 1977b, 1977c, 1981b Teo and Vore 1991). Measurement of serum bile acid levels may provide information regarding biliary excretory function. 

Studies in experimental animals have also shown increased urinary protein accompanied or unaccompanied by histopathological changes of the kidneys following exposure to mirex (NTP 1990) or chlordecone (Larson et al. 1979b). Although these changes are not specific for mirex or chlordecone, measurement of these parameters may provide information about renal damage in exposed populations. 

Cardiovascular Effects. Cardiovascular effects as terminal events were reported in patients dying after dermal and inhalation exposure to 1,2-dibromoethane. One individual also had acute myocardial lesions (Letz et al. 1984). Cardiovascular effects were not identified in humans who died after 1,2-dibromoethane ingestion. These findings in humans were not supported by studies in experimental animals exposed by inhalation, oral, or dermal routes. It is unlikely that humans exposed to low levels of 1,2-dibromoethane will experience adverse cardiovascular effects. 

Subsequent studies in experimental animals have yielded provocative results. Resveratrol is known to extend the lifespan of a number of organisms from yeast to vertebrates. Resveratrol is also known to prevent or slow the progression of cancer, cardiovascular diseases, diabetes, inflammation, and ischemic injuries in experimental animals. In short, the suggestion that resveratrol in red wine may be responsible for favorable outcomes in human health is supported by a number of studies in experimental animals. However, the support is suggestive but certainly not definitive. Carefully controlled clinical trials in people will be required to establish the role, if any, of resveratrol or related small molecules in human health. Such clinical trials are currently underway. 

Substituted azojuracils — The coupling of 5-diazouracil (XXXIX) with certain aminonaphthalene derivatives yielded a number of 5-(4-substituted amino-l-naphthylazo)uracils (XL) which exhibit high schistosomicidal activity against Schistosoma mansoni [334—336]. Compounds of this type were selected from among 500 azo-substituted-heterocyclic compounds after extensive studies in experimental animals [334]. 

DATA FROM STUDIES IN EXPERIMENTAL ANIMALS 3.3.1 Animal Toxicity Studies... 

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. 

Data from studies in experimental animals are the typical starting points for hazard and risk assessments of chemical substances and thus differences in sensitivity between experimental animals and humans need to be addressed, with the default assumption that humans are more sensitive than experimental animals. The rationale for extrapolation of toxicity data across species is founded in the commonality of anatomic characteristics and the universality of physiological functions and biochemical reactions, despite the great diversity of sizes, shapes, and forms of mammalian species. 

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. 

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. 

Previously the LMS model (Section 6.2.1.2) was the most widely adopted approach for low-dose extrapolations for data from studies in experimental animals. More recently, an MOE approach has... 

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. 

Wrenn ME, Taylor GN, Stevens W, et al. 1986. DOE life-span radiation effects studies in experimental animals at University of Utah, Division of Radiobiology. In Life-span radiation effects in animals What can they tell us Conference U.S. Department of Energy, 830951. 

The mechanisms by which 2-PAM exerts its cardiac effects have been studied in experimental animals. At least three classes of action have been attributed to the effects of altered calcium metabolism on autonomic ganglia. A sympathomimetic action of 2-PAM was postulated to explain the increase in blood pressure and the augmented myocardial contractility by one or more of the following mechanisms 2-PAM may not block the release of the endogenous compounds, but may prevent the uptake of catecholamine 1 it may stimulate the release of norepinephrine it Increases myocardial contractility by directly stimulating beta receptors and it increases blood pressure by directly stimulating alpha receptors. 5... 

As mentioned earlier (p. 11), the Monographs are not intended to summarize all published studies. Those studies in experimental animals that are inadequate (e g., too short a duration, too few animals, poor survival see below) or are judged irrelevant to the evaluation are generally omitted. Guidelines for conducting adequate long-term carcinogenicity experiments have been outlined (e.g. Montesano et al, 1986). 

Naltrexone, a relatively long-acting opioid receptor antagonist, blocks the effects at -opioid receptors (see Chapter 31). Studies in experimental animals first suggested a link between alcohol consumption and opioids. Injection of small amounts of opioids was followed by an increase in alcohol drinking, whereas administration of opioid antagonists inhibited self-administration of alcohol. 

Polybrominated Biphenyls. Tlie mechanism by which PBBs enter the blood stream in humans is not known consequently, there are no established methods for reducing absorption. Studies in experimental animals that could identify substances that prevent or delay absorption and that do not represent a toxic risk per se would be valuable. Tliere are no established methods for reducing body burden in humans, but studies in animals and model simulations in humans indicate that reducing body fat markedly increases elimination of PBBs (Domino et al. 1982 Tuey and Matthews 1980). The effect of reduction of body fat (e.g., by dieting and exercising) in PBB-exposed humans has not been fully researched. 

Hypersensitivity reactions are usually idiosyncratic and difficult, if not impossible, to predict in safety evaluation studies in experimental animals or humans. 

In studies in experimental animals, there was a lack of correlation between tissue levels of unchanged paracetamol and the necrosis. Furthermore, when radiolabeled paracetamol was administered, several important findings were noted ... 

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