Nonhuman Species

The major sources of exposure of domestic animals to arsenicals are ingestion of feed contaminated with As from industrial pollution or with residues of As-containing pesticides. Other potential sources of As exposure are drinking water contaminated with iAs or organoAs preparations used as 

With the exception of rats and marmoset monkeys, most experimental species show similar patterns of As methylation. Typically, DMA was found to be the major methylated metabolite excreted in urine together with a smaller fraction present as MMA. The proportion of methylated metabolites and rate of excretion vary among species, depending on route of administration, dosage level, and chemical form of As administered. 

Rabbits injected with l//gAs /kg i.p. excreted 60% of the dose in urine and 6% with feces during the first posttreatment day (Bertolero et al. 1981). iAs was found to be the predominant species in urine during the first 2h posttreatment. At later time points, DMA was the major metabolite (80% of urinary As at 6h). MMA was detected in urine as a minor metabolite ( 5%). MMA, DMA, and iAs were found in plasma in similar proportions. At 6h after injection, the ultrafiltrable fraction of As in cytosol of lung, liver, and kidney from injected animals consisted of 3.6%, 30.1%, and 48.5% of iAs, respectively the portion as DMA reached 95.3%, 68.5%, and 47.6%. MMA ranged between 1.3% and 3.3%. In liver and kidney cytosol, most of the As (70.3%-86.5% of total As) was bound to proteins at 4 and 6h after injection. 

Dose-dependent disposition of As in mice was studied by Hughes and coworkers (1994). An acute p.o. dose (0.5-5000//g/kg) had no effect on the percentage of the dose of As excreted in urine (66%-79%) and in feces (10%-18%). DMA was the predominant urinary metabolite (51%-64% of dose) but no effect of dose on its elimination was detected. However, peak DMA elimination in urine shifted from 4h postexposure at lower dosage levels to 8h at the 5000-//g/kg dose. With increasing dose, a significant increase of the MMA portion in urine (0.1%-1.0% of dose) was observed. At the 5000-//g/kg dose, there was an increase in the amount of arsenate and arsenite in the 1- and 2-h urines. These results suggest that an acute dose of As (5000///kg) can affect the metabolism of arsenicals. 

Treatment with dimercaptans was shown to increase the rate of As excretion in urine of rabbits after s.c. injection of lmgAs /kg (Maiorino and Aposhian 1985). Injection intramuscularly of 2,3-dimercapto-l-propanesulfonic acid (DMPS), me50-2,3-dimercaptosuccinic acid (DMSA), or /V-(2,3-dimercaptopropyl)-phthalamidic acid (DMPA) before As treatment increased the rate of urinary excretion of total As during the first 24 h after administration but did not affect the cumulative amount of As excreted between 0 and 48 h. A change in As species in urine (increased iAs and 

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Couch, J.A., W.P. Schoor, W. Davis, and L. Courtney. 1983. Effects of Carcinogens, Mutagens, and Teratogens on Nonhuman Species (Aquatic Animals). U.S. Environ. Protection Agency Rep. 600/9-83-005. 46 pp. 

Discussions of the value to be attributed to the preservation of a natural system invoke two distinct sources of value extrinsic and intrinsic values. Extrinsic value arises from the fact that the environment increases the satisfaction or utility of humans. In this utilitarian philosophy, nature has value insofar as it is useful or agreeable to humans. The intrinsic value of a natural system exists irrespective of its usefulness or amenity to humans. This view explicitly grants rights to exist to nonhuman species or to the environment as a whole. The intrinsic value approach may thus require decision makers to make decisions knowingly counter to their own present on future interests (Pannell and Schilizzi 1999). 

The appropriateness of testing a human-specific peptide hormone in nonhuman species ... 

In the experimental evaluation of substances for carcinogenesis based on experimental results of studies in a nonhuman species at some relatively high dose or exposure level, an attempt is made to predict the occurrence and level of tumorogenesis in humans at much lower levels. In this chapter we will examine the assumptions involved in this undertaking and review the aspects of design and interpretation of traditional long-term (lifetime) animal carcinogenicity studies as well as some alternative short-term models. 

Remind themselves and others of the possibility of toxic effects not detected because they could not be displayed by the test systems used (e.g., headache in a nonhuman species, or carcinogenicity in a 1 -month experiment), or were not sought. 

Some biotechnologically derived pharmaceuticals will cross-react with species that can be evaluated toxicologically, while others cross-react only with nonhuman primates such as the chimpanzee, a protected species. In this case, a well-designed safety, or Phase 0 study at doses higher than the proposed clinical dose may provide valuable safety information. However, a lack of cross-reactivity with any nonhuman species does not necessarily make preclinical safety evaluation impossible, not does it limit toxicity testing to species in which the protein lacks relevant pharmacological activity. Some alternative possibilities are summarized in Table 12.9. 

Preclinical animal studies are usually performed with simple formulations which are appropriate for the route investigated in the (nonhuman) species involved. While similar simple formulations or approaches (such as capsules) are also employed for first-in-man studies, as development proceeds, efforts are made to develop formulations which optimize bioavailability. This may lead to effects not seen in earlier animal (or, indeed, human) studies, a factor that should be kept in mind in both study design and interpretation. 

Except for short-term hazards from concentrated spiUs, BTEX compounds (benzene, toluene, ethylbenzene, and xylenes) have been more frequently associated with risk to humans than with risk to nonhuman species such as fish and wildlife. This is partly because plants, fish, and birds take up only very small amounts, and because this volatile compound tends to evaporate into the atmosphere rather than persisting in surface waters or soils. However, volatiles such as this compound can pose a drinking water hazard when they accumulate in groundwater. See also BTEX entry, and entries for benzene, toluene, ethylbenzene, and xylenes. 

Many of these wild places and conditions are quite unintended outcomes of our own actions. Urban people are constantly making incidental natures, interacting with nonhuman species to create environmental outcomes of startling complexity. The lesser kestrel, a bird of prey currently on the brink of extinction, thrives in some cities of the Middle East, where it nests in clay roof tiles in areas of urban growth, just as the recovery of the peregrine falcon, a threatened species in the United states, is partly predicated on its New York City... 

As a prodrug, enalapril is essentially inactive as an ACE inhibitor. Thus, it must be enzymatically converted to enalaprilat, and liver homogenates of rats, dogs, rhesus monkeys, and humans have that capacity (128). In humans and in all nonhuman species except the rhesus monkey, deesterification is the only metabolism which is observed. In monkeys, a small amount of the desproline metabolite of enalaprilat has been detected (128). Absorption of enalapril is reported to be 39% in rats, 64% in dogs, and 60-70% in humans (128). 

Because the enlarged cortex of humans is not shared by most nonhuman species, using animal models to study the functions of the cortex is more difficult. Much of what we know about the cerebral cortex then has come V from unfortunate accidents and diseases such as strokes... 

Although receptor studies have required the use of nonhuman species (principally the mouse but also Ihe rat. cow. sheep, and rabbit I. a high correlation of structural homology of receptor subtypes between species (—80 to 9nVr) has been observed, while structural homology among receptor sub-... 

The animal welfare and animal rights movements can both be seen as part of a centuries-old movement toward pan-species democratization - toward the view that nonhuman species have a fundamental place in nature and a basic right to lead their own lives. 

The Canadian Environmental Protection Act, 1999 (CEPA 1999) requires the Ministers of the Environment and Health to categorize the substances on the Canadian Domestic Substances List (DSL). The DSL contains 23 000 substances that are subject to categorization (i.e., prioritization). Generally the data selection process involves a search of the scientific literature and databases for quality experimental data for persistence, bioaccumulation potential and inherent toxicity to humans and nonhuman species. If acceptable data are not found, QSARs or other models are used to estimate the persistence, bioaccumulation, and aquatic toxicity of substances based on structure and physical - chemical properties. 

The subarea of risk assessment that deals with the effects of chemicals upon the environment is known as environmental risk assessment or ecological risk assessment. This subarea deals with effects on nonhuman species and entire ecological systems on landscape and regional scales. Risk assessment as applied to environmental toxicology is discussed extensively in Chapter 12. 

Several compounds, e.g., vitamin D and niacin, are apparently required in the diet even though pathways for their synthesis occur in the body. Such a situation may arise if a pathway does not provide an adequate supply for the body s needs or if the material cannot be readily transported from the site of synthesis to the place of action. The compounds discussed below are essential dietary nutrients in one or more nonhuman species, but such a status in humans is not supported by evidence. 

The observations that fetal tissues in culture produce somatomedins (Section 2.1), and that receptors for somatomedins (especially IGF-II) are abundant in membranes of fetal tissues (Section 4.3), both suggest that somatomedins may play a role in fetal development. Hus is supported by measurements of the peptides in the fetal circulation. While some early studies in this area are inconclusive due to the broad cross-reactivities of the assay methods employed, specific determination of SM-C/ICF-I and IGF-II levels has been possible in recent studies, although much of the fetal data is derived from nonhuman species. 

Influenza viruses. These negative-stranded viruses are classified into types A, B, and C, but it is only type A that infects nonhuman species including birds, horses, pigs, seals, mink, and whales. ... 

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