Differences in toxicity

Fig. 3. Schematic representation showing the anatomical basis for differences in the quantitative supply of absorbed material to the Hver. By swallowing (oral route), the main fraction of the absorbed dose is transported direcdy to the Hver. FoUowing inhalation or dermal exposure, the material passes to the pulmonary circulation and thence to the systemic circulation, from which only a portion passes to the Hver. This discrepancy in the amount of absorbed material passing to the Hver may account for differences in toxicity of a material by inhalation and skin contact, compared with its toxicity by swallowing, if metaboHsm of the material in the Hver is significant in its detoxification or metaboHc activation.

Technical-grade endosulfan contains at least 94% a-endosulfan and (3-endosulfan. The a- and (3-isomers are present in the ratio of 7 3, respectively. The majority of the studies discussed below used technical-grade endosulfan. However, a few examined the effects of the pure a- and (3-isomers. Endosulfan sulfate is a reaction product found in technical-grade endosulfan as a result of oxidation, biotransformation, or photolysis. There is very little difference in toxicity between endosulfan and its metabolite, endosulfan sulfate. However, the a-isomer has been shown to be about three times as toxic as the P-isomer of endosulfan. 

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

Besides melanoma cells with the extraordinary sensitivity towards AU55, the difference in toxicity is also very obvious for Hek-12 and U-20S where the effectiveness of AU55 is 32 and 18 times higher than that of cisplatin. 

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... 

Relating the effects caused by specific allelochemicals to those caused by an allelopathic plant is complicated because the inhibitory substances released from a plant are often unknown, and generally several different compounds are involved. However, the actions of the weeds studied in our investigations have certain parallels to those found from pCA and FA. The allelopathic nature of Kochi a, Jerusalem artichoke, and cocklebur was established, since both aque-ous extracts and weed residues reduced sorghum growth. The data show a concentration dependency characteristic of allelopathy, and some difference in toxicity among the three weeds was observed with cockle-bur the most toxic. 

The provocative initial biological activities reported for PatA, primarily the 20,000-fold difference in toxicity toward cancer cells (P388) versus a quiescent cell line (BSC) (Northcote et al, 1991), led us to undertake a total synthesis of this natural product that would ultimately enable detailed mode of action studies. We envisioned the synthesis and subsequent union of three principal fragments, namely, enyne acid 4, /1-lactam 10, and dienylstannane 14 (Fig. 14.1). A crucial aspect of this plan was a late-stage Stille coupling to append the expected labile trienyl... 

If the test article is an enantiomer isolated from a mixture that is already well characterized (e.g., already on the market), then appropriate bridging guides need to be performed which compare the toxicity of the isomer to that of the racemic mixture. The most common approach would be to conduct a subchronic (three months) and a Sement II-type teratology study with an appropriate positive control group which received the racemate. In most instances no additional studies would be required if the enantiomer and the racemate did not differ in toxicity profile. If, on the other hand, differences are identified, that the reasons for this difference need to be investigated and the potential implications for human subjects need to be considered. 

Different routes of administration yielding differences in toxicity Plasma levels of test article... 

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. 

Persons with a history of convulsive disorders would be expected to be at increased risk from exposure to endrin. Children may be more sensitive than adults to the acute toxic effects of endrin. In an endrin poisoning episode in Pakistan, children 1-9 years old represented about 70% of the cases of convulsions (Rowley et al. 1987). The causative factor responsible for the outbreak was not identified, however, and the age distribution of cases could be explained by age-specific exposure situations. In general, following oral administration, female animals appear to be more susceptible to endrin toxicity than males (Gaines 1960 Treon et al. 1955). The difference may be due to the more rapid excretion of endrin by male versus female rats (Hutson et al. 1975 Klevay 1971 Korte et al. 1970). A sex-related difference in toxicity was not apparent following dermal exposure (Gaines 1960, 1969). No sex-based differences in endrin-related... 

This difference in toxicities when using saline and propylene glycol should be noted when comparing potencies. 

Comparative Toxicokinetics. No data are available to determine if there are differences in the toxicokinetics of 1,2-diphenylhydrazine among species. Toxicokinetic studies with different species could help explain observed differences in toxicity and carcinogenicity between rats and mice, and help identify the animal species that serves as the best model for extrapolating results to humans. 

Toxicokinetic data The major factors responsible for differences in toxicity due to route of exposure include (1) differences in bioavaUabUity (absorption), (2) differences in metabolism (e.g., first-pass effects), and (3) differences in internal exposure pattern (kinetics). 

Tbxaphene is a mixture of at least 670 chlorinated camphenes differences in toxicity have been observed for various toxaphene fractions or components. ... 

Specific differences in toxicity toward each test species were discovered between the various plant chemical arrays. Table HI lists survivorship for these species for alkaloid-producing cacti. Additionally, data was obtained for 20 species in which alkaloids were not detected. The three insect species showed consistent differences in tolerance toward given plant species, with no clear phylogenetic pattern accounting for this. Insects also responded differently to aikaloidal fractions versus triterpenoid glycoside fractions. Alkaloids were found to be generally not toxic to D. 

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