Mouse studies

Oral administration of 11.6 mg/kg/day of endosulfan to rats for up to 30 days also failed to induce chromosomal damage in bone marrow and spermatogonial cell systems, but it is not known how soon after treatment the animals were killed. As shown in mouse studies (Usha Rani and Reddy 1986), a latency period of 60 days was required to see chromosomal aberrations in spermatogonia. However, relatively significant changes were observed for mitotic indices (Dikshith et al. 1978). 

Mice exposed to 2,000 ppm of trichloroethylene, 4 hours/day for a 5-day period, had a significant increase in abnormal sperm morphology of 1% 28 days after the exposure (Land et al. 1981). No effect was seen at 200 ppm. A 6% increase in abnormal sperm was observed 4 weeks, but not 4 days or 10 weeks, after mice were exposed to 100 ppm trichloroethylene 7 hours per day for 5 days (Beliles et al. 1980). Based on the time after exposure at which sperm were affected, the study authors indicated that trichloroethylene damages sperm precursor cells but that spermatogonia were either unaffected or were capable of recovery. Reproductive performance was not tested in these studies. Another mouse study tested the effects of a 5-day exposure (6 hours/day) on spermatid micronuclei frequency no effects were observed at exposure levels of up to 500 ppm, the highest concentration tested (Allen et al. 1994). These results were interpreted as evidence that trichloroethylene did not cause meiotic chromosome breakage or loss. No treatment-related reproductive effects were seen in female rats exposed to 1,800 ppm trichloroethylene for 2 weeks (6 hours/day, 7 days/week) before mating (Dorfmueller et al. 1979). 

As might be expected from the results of the IL-10 / mouse study, ES-62 is able to induce production of IL-10 in naive BALB/c spleen cells (Harnett et al, 1999a). Although we have not investigated whether this is due to the PC component of the molecule, this would be predicted from the work of Hoerauf and colleagues, who showed that PC causes release of this cytokine from B1 cells (Palanivel et al, 1996 AlQaoud et al, 1998). However, we have also found, as mentioned earlier, that ES-62 promotes the release from naive spleen cells of IL-12 and, in addition, IFN-y -... 

Although several data sets were available to derive AEGL-2 values, the 1-h exposure data from the mouse study by Peterson and Bhattacharyya (1985) provided the most sound basis. 

Although several data sets could be used to derive AEGL-3 values, the 1-h exposure data from the mouse study by Peterson and Bhattacharyya (1985) provided the most sound basis and were selected to derive AEGL-3 values. Due to the steep concentration-response curve for arsine, the 15-ppm exposure (where there was no lethality) was considered an estimate of the lethality threshold. An uncertainty factor of 30-fold was applied to account for interspecies extrapolation (10-fold) and intraspecies variability (3-fold) (see Section 6.3). 

Rothstein, I. D. Of mice and men reconciling preclinical ALS mouse studies and human clinical trials. Ann. Neurol. 53 423 26,2003. 

Compared to people in a noncontaminated area, plasma IgG levels were also significantly decreased in proportion to increasing plasma levels of TCDD in a cohort exposed in an industrial accident in Seveso, Italy.118 There was no effect on IgM or IgA levels, or on complement levels IgE was not measured. In separate studies, in vitro exposure to TCDD enhanced the spontaneous production of IgE by B cells isolated from atopic but not non-atopic individuals, but did not affect the levels of other isotypes.119 Other recent studies have reported small changes in immune cells from individuals exposed occupationally to PHAH.120121 For example, compared to unexposed controls, a cohort of men exposed occupationally to TCDD had diminished IFNy production in a recall response to tetanus toxin, while IFNy production following polyclonal activation was unaffected.120 This observation is consistent with mouse studies, in which antigen-specific responses are highly suppressed by TCDD, but mitogen-driven T cell responses are less susceptible to impairment.83 88122123... 

Crestani, F., Martin, J. R., Mohler, H., and Rudolph, U. (2000) Resolving differences in GABAA receptor mutant mouse studies. Nat. Neurosci. 3,1059. 

In the rat and mouse studies by Higgins et al. (1972) and the rat and rabbit studies by Ballantyne (1983), LC50 values differed by less than a factor of two... 

There has been extensive debate and consideration on the relevance and value of the traditional long-term rodent bioassays. The FDA looked at rat and mouse studies for 282 human pharmaceuticals, resulting in the conclusion that sufficient evidence is now available for some alternative in vivo carcinogenicity models to support their application as complimentary studies in combination with a single two-year carcinogenicity study [emphasis added] to identify trans-species tumorigens (Contrera et al., 1997). 

The duration of carcinogenicity studies for both rats and mice is two years in most pharmaceutical laboratories (PMA, 1988). Occasionally, rat studies are extended to 30 months, while some companies terminate mouse studies at 18 months. The difference in duration between mouse and rat studies is based on the behef that rats have a longer natural hfe span than mice. Recent data indicate, however, that this is not the case. The most commonly used strains, the Sprague-Dawley rat and the CD-1 mouse, have approximately equal survival at two years, based on industry data (PMA, 1988). The same is true for the most popular inbred strains, the Fischer 344 rat and the B6C3F1 mouse (PMA, 1988). Data from NCI studies confirm that the two-year survival of the B6C3F1 mouse is at least equal to, if not greater than, that of the Fischer 344 rat (Cameron et al., 1985). 

The relevance (and return on investment) for the bioassays preformed in mice have been questioned for some time. In 1997, ICH opened the possibility for the substitution of some form of short- or medium-term mouse test as an alternative for the traditional lifetime mouse bioassay. FDA has subsequently stated that it would accept validated forms of a set of medium-term mouse studies based on transgenic models, and significant effort has since gone into such validation. 

Acetylation also plays a role in mitochondrial function and basal levels of ATP. Mouse studies have shown that in mice lacking a deacetylase (Sirt3), basal ATP levels were lower than that in normal mice. In organs such as the heart, kidneys, and liver, the ATP levels were decreased more than 50%. In concurrence with lower ATP levels, higher acetylation levels of mitochondrial proteins were also noted. When Sirt3 was added, ATP levels returned to normal. This work leads to the conclusion that acetylation controls the levels of ATP in the cell. 

Absorption, Distribution, Metabolism, and Excretion. Human data indicate that chloroform absorption from the lungs is rapid and fairly complete (Smith et al. 1973). The data also indicate that absorption after oral exposure is fairly complete for both animals and humans (Brown et al. 1974a Fry et al. 1972 Taylor et al. 1974). Although there are no experimental data regarding dermal absorption in humans, some data have been extrapolated from mouse studies (Tsumta 1975). The rate of absorption following oral or inhalation exposure is rapid (within 1-2 hours). Additional animal studies investigating the rate of dermal absorption would be useful to quantitate dermal absorption and to compare information from oral and inhalation studies. 

There are data from animal studies in mice, rats, and pigs that indicate that both carbohydrate metabolism and lipid metabolism may be affected by exposure to heptachlor or heptachlor epoxide (Enan et al. 1982 Halacka et al. 1974 Kacew and Singhal 1973 Pelikan 1971). Alterations in gluconeogenic enzymes and an increase in cellular steatosis in the liver have been reported. Granulomas and fibrotic liver have also been observed. In addition, hepatocellular carcinoma was identified as causally related to heptachlor in the diet in a mouse study conducted by the National Cancer Institute (NCI 1977). The existing evidence suggests that heptachlor and heptachlor epoxide are hepatic toxicants. 

Finally, mouse studies have confirmed the hypothesis that RUNXl mutations are initiating events - but require secondary mutations for acute leukemia induction. A major emphasis of current work is to determine what type of mutations collaborate with RUNXl mutations to induce an acute leukemia. Screening of patient samples have underlined the importance of mutations in receptor tyrosine kinases (RTK) in these leukemia. Interestingly, mutations in the KIT receptor are relative rare in AML, but reach an incidence of circa 45% in AML with CBF mutations, perhaps reflecting high levels of KIT expression... 

In one series of studies (NTP 1987), the lethality data for 1,4-dichlorobenzene, when administered for 14 days by gavage in com oil to Fischer 344 rats and B6C3Fi mice, were rather inconsistent. In one of these studies, no 1,4-dichlorobenzene-related deaths occurred in rats of either sex that received doses up to 1,000 mg/kg/day however, in the second rat study, 4 of 5 females (80%) at 1,000 mg/kg/day died, and all rats dosed at >2,000 mg/kg/day died. In one 14-day study in mice, no 1,4-dichlorobenzene-related deaths occurred in either sex at levels up to 1,000 mg/kg/day however, in a second 14-day mouse study, 70% of mice at 1,000 mg/kg/day died, and all mice that received 4,000 mg/kg/day died within 4 days. At... 

The authors also noted that the database for the derivation of a standard value is very limited. The few available data support a factor of 2-3 additional (multiplicatively) to the scaling factor in order to cover, for approximately 95% of the substances (i.e., the 95th percentile), a possibly greater sensitivity of humans compared with experimental animals. The overall interspecies assessment factor would then be 8-12 for a rat study and 14—21 for a mouse study. 

Additional animals will be required to provide pharmacokinetic information, especially in mouse studies where blood sampling sufficient for analysis usually requires the animal to be killed. 

Chrysene was mutagenic to Salmonella typhimurium in the presence of an exogenous metabolic system. It induced sister chromatid exchanges in one mouse study and chromosomal aberrations in one hamster study. Chrysene is metabolically activated to a 1,2-diol-3,4-epoxide that is mutagenic and carcinogenic in experimental animals and forms covalent adducts with DNA. ... 

Peroxy derivatives of steroids have been isolated from both marine and terrestrial sources. They are most commonly 5a, 8a-endoperoxides with variations in the side-chains. The ergosterol peroxide 102 is the most ubiquitous endoperoxide-containing natural product and is isolated from a large number of sources. Ergosterol peroxide 102 was found to have antitumour activity against breast cancer and carcinosarcoma cell lines. A number of other steroidal endoperoxides have been reported which differ in the nature of the side-chain. Compound 103 was found to be an inhibitor of tumour promotion in mouse studies . 

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