Species differences in toxicity

Species Differences. Species differences in metabolism are amongst the principal reasons that there are species differences in toxicity. Differences in cytochrome P450 is one of the most common reasons for differences in metabolism. For example, Monostory et al. (1997) recently published a paper comparing the metabolism of panomifene (a tamoxifen analog) in four different species. These data serve to address that the rates of metabolism in the non-human species was most rapid in the dog and slowest in the mouse. Thus, one should not a priori make any assumptions about which species will have the more rapid metabolism. Of the seven metabolites, only one was produced in all four species. Both the rat and the dog produced the two metabolites (M5 and M6) produced by human microsomes. So how does one decide which species best represents humans One needs to consider the chemical structure of the metabolites and the rates at which they are produced. In this particular case, M5 and M6 were relatively minor metabolites in the dog, which produced three other metabolites in larger proportion. The rat produced the same metabolites at a higher proportion, with fewer other metabolites than the dog. Thus, in this particular instance, the rat, rather than the dog, was a better model. Table 18.8 offers a comparison of excretion patterns between three species for a simple inorganic compound. 

There are many different examples of species differences in the toxicity of foreign compounds, some of which are commercially useful to man, as in the case of pesticides and antibiotic drugs where there is exploitation of selective toxicity. Species differences in toxicity are often related to differences in the metabolism and disposition of a compound, and an understanding of such differences is extremely important in the safety evaluation of compounds in relation to the extrapolation of toxicity from animals to man and hence risk assessment. 

Absorption. Absorption of foreign compounds from various sites is dependent on the physiological and physical conditions at these sites. These, of course, may be subject to species variations. Absorption of compounds through the skin shows considerable species variation. Table 5.2 gives an example of this and shows the species differences in toxicity of an organophosphorus compound absorbed percutaneously. Human skin is generally less permeable to chemicals than that of rabbits, mice, and rats, although there is variation. For some compounds, rat skin has similar permeability to human skin and seems to be less permeable than that of the rabbit. 

In some cases, species differences in toxicity are due to more than one metabolic difference. For example, research on the fungal toxin aflatoxin B1 indicates that humans are particularly susceptible, more so than rodents, with rats being more susceptible than mice. Interestingly, cynomologous monkeys are also relatively insensitive probably due to the lack of constitutive CYP1A2. 

The absorption, distribution, metabolism, and excretion in the species used in the toxicology studies should be discussed. Quantitative or notable qualitative differences in ADME between the various animal species and humans should be discussed, as well as any references to observed species differences in toxicity and extrapolation of the findings to humans. The significance of these findings to the interpretation of the results of the carcinogenicity, bioassay, and other preclinical toxicity studies should be considered. 

Bom S, Caudill D, Smith BJ, and Lehman-McKeeman LD (2000) In vitro kinetics of coumarin 3,4-epoxidation Application to species differences in toxicity and carcinogenicity. Toxicological Sciences 58 23-31. 

Abnet, C.C., R.L. Tanguay, W. Heideman and R.E. Peterson. Transactivation activity of human, zebrafish, and rainbow trout aryl hydrocarbon receptors expressed in COS-7 cells greater insight into species differences in toxic potency of polychlorinated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners. 

The rate of bile secretion and the pH of the bile may also be determinants of the extent of biliary excretion of a foreign compound, and these also show species variations. The fate of compounds excreted in the bile may also depend on the species, as differences in intestinal pH and flora occur. A particularly important consequence of biliary excretion is metabolism by the gut flora and reabsorption. This enterohepatic circulation prolongs the length of time the animal is exposed to the foreign compound, and may introduce novel toxic metabolites. This could therefore result in marked species differences in toxicity. 

N. Millichamp. Factors affecting the interpretation of species differences in toxic responses of ocular... 

Exposure studies have been made using mice and rats (257). These experiments have demonstrated species differences in butadiene toxicity and carcinogenicity. Butadiene was found to be a potent carcinogen in the mouse, but only a weak carcinogen in the rat. The interpretations have focused on differences in toxification rates and detoxification metaboHsms as causative factors (257). The metaboHsm is beHeved to proceed through intermediates involving butadiene monoepoxide and butadiene diepoxide (257). A similar mechanism has been proposed for its biodegradation pathway (258). 

Chambers JE, Carr RE. 1995. Biochemical mechanisms contributing to species differences in insecticidal toxicity. Toxicology 105 291-304. 

Thompson HM, Langton SD, Hart ADM. 1995. Prediction of inter-species differences in the toxicity of organophosphorus pesticides to wildlife—a biochemical approach. Comp Biochem Physiol 111C 1-12. 

In general, it is easier to use models such as these to predict the distribution of chemicals (i.e., relationship between exposure and tissue concentration) than it is to predict their toxic action. The relationship between tissue concentration and toxicity is not straightforward for a diverse group of compounds, and depends on their mode of action. Even with distribution models, however, the picture can be complicated by species differences in metabolism, as in the case of models for bioconcentration and bioaccumulation (see Chapter 4). Rapid metabolism can lead to lower tissue concentrations than would be predicted from a simple model based on values. Thus, such models need to be used with caution when dealing with different species. 

Selective toxicity (selectivity) Difference in toxicity of a chemical toward different species, strains, sexes, age groups, etc. 

Chronic-Duration Exposure and Cancer. No data were located regarding chronic-duration exposure of humans or animals to americium. Chronic-duration inhalation and oral MRLs were not derived for americium due to the lack of human or animal data. To generate appropriate data for deriving chronic-duration inhalation and oral MRLs for americium, at least one comprehensive chronic-duration inhalation and one chronic-duration oral toxicity study of at least one animal species exposed to several dose levels would be needed. Such studies could be designed to also generate data regarding potential age-related differences in toxicity. However, since americium is not found naturally, and is produced and used... 

Kleeman, J.M., J.R. Olson, and R.E. Peterson. 1988. Species differences in 2.3.7.8-tctrachIorodibenz.o-p-d 10xin toxicity and biotransformation in fish. Fundament. Appl. Toxicol. 10 206-213. 

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