Differences between human and

Traditional views would have led to the expectation that considerable differences between humans and other animals would have been found in a construction linked... 

Species differences between humans and animals are avoided. 

Differences between humans and other organisms In humans, chemicals are used In other organisms, chemicals are used... 

For in vivo studies, animal models are set up and how the target is involved in the disease is analyzed. One such model is the use of knockout or transgenic mice (Exhibit 2.8). It should be borne in mind, however, that there are differences between humans and animals in terms of gene expression, functional characteristics, and biochemical reactions. Nevertheless, animal models are important for the evaluation of drug-target interactions in a living system. 

The Renwick work can be applied in the following way. Suppose it were possible in a specific case to develop a reasonably thorough picture of the comparative pharmacodynamic characteristics of a compound in humans and rats, and that the work revealed that no difference in pharmacodynamic response (at comparable doses) was expected. We would then turn to Table 9.1 and see that the typical pharmacodynamic difference between humans and animals (the default) puts humans at 2.5 times greater risk than animals. But now in our new case, the difference is seen to be a factor of 1.0 (no difference). We should be allowed to reduce the overall UF of 10 to a factor of 4.0, which is the default for pharmacokinetic differences (which we have not studied). Data substitute for defaults. Use of the Renwick defaults allows us to make some headway without having to take on... 

Above I noted that DNA sequences of the genomes of man and chimps are about 99% the same. Those sequences for the genomes of man and mouse are about 98.7% the same. What is the meaning for these apparently very modest differences at the level of the essential molecules of life In fact, the commonly cited figure of a 1% difference between humanness and chimpness may be more misleading than useful. It does serve to indicate just how closely we really are related. 

Note the difference between humans and deer. (Redrawn from various sources.)... 

Our next consideration is DNA repair. One tenet of the short-term testing business today is that there does not seem to be any reason to expect differences among mice, rats, and humans. In fact, there are important differences between humans and... 

Walton et al. (2004) determined the extent of interspecies differences in the internal dose of compounds, which are eliminated primarily by renal excretion in humans. Renal excretion was also the main route of elimination in the test species for most of the compounds. Interspecies differences were apparent for both the mechanism of renal excretion (glomemlar filtration, tubular secretion, and/or reabsorption), and the extent of plasma protein binding. Both of these may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which were eliminated unchanged by both humans and the test species, the average difference in the internal dose between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats, and 13 for mice. This suggests that for renal excretion the differences between humans and the rat, and especially the mouse, may exceed the fourfold default factor for toxicokinetics. 

Bioavuilubility is a measure of a substance s availability within the body following external exposure. It is mainly governed and influenced by route-specific absorption rates. It may differ between humans and experimental animals. Consequently, if information is available indicating species-specific differences in bioavailability for the same exposure route, the dose descriptor has to be corrected accordingly. 

There is empirical evidence for interspecies differences between humans and experimental animals. These arise from differences in caloric demand (26), toxicokinetics as well as toxicodynam-ics and are usually taken into account for the DNEL derivation by application of appropriate assessment factors. 

Natsume, M. et al., Structures of (—)-epicatechin glucuronide identified from plasma and urine after oral ingestion of (—)-epicatechin differences between human and rat. Free Radical Biol. Med., 34, 840, 2003. 

Therefore in practice, normally, animal toxicity data is required (see above). Of course, the differences between humans and other species must always be recognized and taken into account (see below). It may be possible to use in vitro data both from human cells and tissues as well as those from other animals to supplement the epidemiological and animal in vivo toxicity data. However, at present such data cannot replace experimental animal or human epidemiological data. The predictive use of structure-activity relationships is also possible, and it is an approach, which is becoming increasingly important. 

The blood levels of 1,1,1-trichloroethane in human subjects were lower following exposure to 350 ppm [1910 mg/m ] (approximately 2 mg/L) (Nolan et al., 1984) than those found in rats and mice following exposure to 150 ppm [820 mg/m ] (9.6 mg/L and 12.6 mg/L, respectively) (Schumann et al., 1982b). The species differences between humans and rats are probably the result of a lower 1,1,1-trichloroethane blood air partition coefficient and greater adipose tissue volume in humans (Dallas et al., 1989). 

Eckhert, C. D., Sloan, M. V., Duncan, J. R. and Hurley, L. S. 1977. Zinc binding A difference between human and bovine milk. Science 195, 789-790. 

Aj receptor within mammals (Fig. 3.1a) contrasts the much larger differences seen for the A3 subtype (Fig. 3.1b). In fact, the differences between human and rat A3 are similar to the differences seen between human and the non-mammalian chick A receptors. Although the pronounced sequence differences between mammalian A3 receptors may help to explain the striking discrepancy of pharmacological characteristics between receptors in different species, it does not seem to be sufficient to account for the particularly dramatic distinction of antagonist binding to rat and human subtypes (Klotz 2000). 

Estimates of responses at low doses derived from data on laboratory animals and extrapolated to humans are complicated by a variety of factors that differ among species and potentially affect the response to hazardous chemicals. These factors include differences between humans and experimental test animals with respect to life span, body size, genetic variability, population homogeneity, existence of concurrent disease, such pharmacokinetic effects as metabolism and excretion patterns, and the dosing regimen. These factors are discussed further in Section 3.2.1.5. 

Additional bioassays in animals do not seem necessary. Further research on dose-response relationships for the many biochemical effects of peroxisome proliferators leading to liver cancer in rodents, identification of specific thresholds, and potential reversibility, would be informative only if an extrapolation model for cancer was deemed appropriate in spite of profound differences between human and rodent responses. 

Approaches to duration adjustment are reviewed in Kimmel et al. (2006). Prior to derivation of NOAELs, LOAELs, or BMDs/ BMCs, the toxicity data are adjusted to a continuous exposure scenario. For oral studies, a daily exposure adjustment is made (e.g. a five days per week exposure is converted to seven days per week). For inhalation exposures, a concentration x time (c x t) adjustment is made. Traditionally, the inhalation exposure adjustment has not been done, because of concerns about peak versus integrated exposure and the likelihood of a threshold for effects. However, a review of the RfD and RfC processes by the USEPA recommended that inhalation developmental toxicity studies be adjusted in the same way as for other end-points (USEPA, 2002b). Derivation of a human equivalent concentration for inhalation exposures is intended to account for pharmacokinetic differences between humans and animals. 

A major difference between human and rabbit plasma is that the latter has less and possibly different lipoproteins. If the hypothesis that lipoproteins affect the extraction efficiency for A9-THC is correct, this could explain the somewhat higher extraction efficiencies from plasma. These results support Mechoulam s argument that, in the analysis of A9-THC in plasma, it may be necessary to consider the biological source of the plasma (3). 

When quantitative absorption data for a route of exposure indicate differences between humans and the relevant test species, the no-observed-adverse-effect level (NOAEL) might need to be adjusted proportionately. 

When data are insufficient to determine the relative susceptibility of animals in comparison to humans, a UF of 10 has been used by EPA, ATSDR, Health Canada, WHO, the International Programme on Chemical Safety (IPCS), and Rijksinstituut voor Volksgesondheid en Milieu (RIVM) when developing the equivalent reference doses for chronic exposure to chemicals (Dourson et al 1996). When extrapolations are made from animals to humans based on milligrams per kilogram of body weight, the factor of 10-fold is usually adequate to account for differences in response. Dourson and Stara (1983) found that a factor of 10 accounted for many of the animal-to-human differences observed when the dose was adjusted for differences between human and animal body weights and body-surface areas. 

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