Differences in species

On the basis of these differences in species response it was concluded that phthalates do not pose a significant health hazard to humans. This view is home out by the EU Commission decision of July 25, 1990 which states that DEHP shall not be classified or labeled as a carcinogenic or an irritant substance (42). This has been reaffirmed in a comprehensive review (43) which concludes that "peroxisome proliferators constitute a discrete class of nongenotoxic rodent hepatocarcinogens and that the relevance of thek hepatocarcinogenic effects for human hazard assessment is considered to be negligible."... 

Hepatic peroxisome proliferation, characterized by liver enlargement due to hyperplasia and hypertrophy, has been proposed as a basis for differences in species susceptibility to trichloroethylene carcinogenicity. Peroxisomes are membrane-bound organelles which contain enzymes generally involved in lipid metabolism. 

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. 

The relative toxicity, especially of the newer compounds, to various pests and species is of practical importance, as are also differences in species tolerance to DDT and other sprays. This is also of direct concern in relation to parasites and predators. There is interest in synergistic action and the effect of spreaders, stickers, and related products. The effect and use of repellents and attractants have received attention. 

Dogs were more susceptible to neurotoxicity from hexachloroethane vapors than rats, and both species were more sensitive than guinea pigs and quail (Weeks et al. 1979). Pregnant rats were more sensitive to tremors than nonpregnant rats (Weeks et al. 1979). Once the mechanism of neurotoxicity has been determined, the advisability of examining differences in species response can be evaluated. 

Comparative Toxicokinetics. There are limited data on the kinetics of endrin in humans. Studies in animals suggest that metabolism and urinary metabolite profiles vary among species (Baldwin et al. 1975 Hutson et al. 1975 Kanja et al. 1992 Spicer and Kereu 1993). Additional studies using all three potential routes of human exposure would be useful in understanding differences in species and in determining which animal species is the most appropriate model for human exposure. 

Although the metabolism of several phthalate esters has been studied in vitro, essentially all of the in vivo studies have involved DEHP. A summary of these experiments which involved exposure offish to aqueous - C-DEHP is presented in Table IV (11,12). Tissue C was isolated and separated into parent and the various metabolites by preparative thin layer chromatography on silica gel. Metabolites were hydrolyzed where appropriate and identified by gas chromatography-mass spectroscopy. In whole catfish, whole fathead minnow and trout muscle, the major metabolite was the monoester while in trout bile the major metabolite was the monoester glucuronide. The fact that in all cases the major metabolite was monoester or monoester glucuronide despite the differences in species, exposure level and duration, etc. represented by these data, suggests that hydrolysis of DEHP to monoester is important in the biotransformation of DEHP by fish. 

For oral exposures, different fuel oils have differing lethality profiles in rats. Acute lethal doses in rats were reported to be 12,000 mg/kg for kerosene (Muralidhara et al. 1982) and 47,300 mg/kg for JP-5 (Parker et al. 1981). However, an oral dose of 12,200 mg/kg of Deobase was not lethal in rats (Muralidhara et al. 1982). Although differences in the oral toxicity of fuel oils and differences in species thresholds of toxicity may exist, the oral toxicity of fuel oils is relatively low. The intestinal absorption of fuel oils is also relatively low, and aspiration, with its resultant pulmonary effects, is the primary risk from the ingestion of fuel oils. 

Marked differences in species susceptibility to 7 -DNB have also been observed." Hamsters showed no testicular lesions at dose levels up to 50mg/kg, whereas damage to rat testicular tubules was readily apparent at 25mg/kg. Similarly, -DNB induced substantially less methemoglobin in the hamster than in the rat (15% vs. 80% at 25 mg/kg dose). 

Human toxicity data, especially the median lethal dose, is extrapolated from animals or from accidental poisoning, homicides and suicides. Extrapolations from animal data are educated estimates which consider the differences in species and building in a safety factor. If a lethal dose is 10 mg/kg in a rat and we consider a human to be 10 times more sensitive 1 mg/kg will have another 10-fold safety margin. Animal testing also involves using what may seem as ridiculous doses in order to cover the safety factor. To find a statistically valid effect which occurs once in one million subjects, several million animals would have to be used, which is exhorbitantly... 

Cereals (wheat, barley, triticale, rye) Organic practices (lower fertility, no pesticides) No difference in epigeic collembolan composition No difference in species richness of butterflies, rove beetles, spiders, lower richness of carabids Alvarez et ai. (2001) Weibull et ai. (2003)... 

Kajbaf M, Jahanshahi M, Lamb JH, Gorrod JW, Naylor S (1992) Bioanalytical applications of tandem mass spectrometry in the in vitro metabolism of the anticholinergic drug cimetropium bromide to detect differences in species metabolism. Xenobiotica 22 641-655... 

Elmegaard N, Jagers op Akkerhuis GAJM. 2000. Safety factors in pesticide risk assessment differences in species sensitivity and acute-chronic relations. NERI Technical. No. 325. Silkeborg (Denmark) National Environmental Research Institute, Department of Terrestrial Ecology, 60 p. 

The use of the subchronic rat smdy for developing an oral RfD for GB is complicated by the fact that rodents have a much lower RBC-AChE activity level compared to humans (Elhn, 1981, see Table 1). By itself, this could cause rats to be relatively more sensitive than humans to anticholinesterase compounds however, the lower RBC-ChE activity may be offset by the presence of aliesterases in rat blood. Aliesterases, which are not present in humans (Cohen et al., 1971), are known to bind to and thereby reduce the toxicity of GB (Eonnum and Sterri, 1981). Other species differences, such as the rates of aging of the GB-ChE complex, the rates of synthesis of plasma cholinesterase in the liver, and the levels of AChE in various parts of the nervous system (see Ivanov et al., 1993) may also result in differences in species sensitivities. There is insufficient dam to determine the relative susceptibilities of humans and rodents to GB therefore, for the purpose of this assessment, the EPA method will be followed which assumes that humans may be as much as ten times more sensitive to a chemical than laboratory animals. 

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