Rodents studies

The International Agency for Research on Cancer (lARC) has classified DEHP (44) as "an agent possibly carcinogenic to humans." However this classification is based only on the rodent studies and does not take into account the more recent understanding of the underlying mechanisms. 

Neuroendocrine determinants of stress have been found in rodent studies linking endothelial cell responses to hormonal regulation of the HS response (Blake et al., 1991). When rats are physically restrained some of their tissues elaborate HS genes. 

In rodents, a greater proportion of nervous system development takes place postnatally than in humans. Accordingly, rodent studies of developmental neurobehavioral toxicity that extend exposure into the early postnatal period are probably more analogous to human prenatal exposure than are rodent studies that use only prenatal exposure. 

Chronic and subchronic toxicity studies are conducted to define the dose level, when given repeatedly, that cause toxicity, and the dose level that does not lead to toxic findings. In Japan, such studies are referred to as repeated-dose toxicity studies. As with single-dose studies, at least two animal species should be used, one rodent and one nonrodent (rabbit not acceptable). In rodent studies, each group should consist of at least 10 males and 10 females in nonrodent species, 3 of each sex are deemed adequate. Where interim examinations are planned, however, the numbers of animals employed should be increased accordingly. The planned route of administration in human subjects is normally explored. The duration of the study will be dictated by the planned duration of clinical use (Table 2.14). 

These components would normally be evaluated in a rodent species (preferably rats) and, in addition, embryo-fetal development would be evaluated in a second species, typically the rabbit. The most probable option in the ICH guideline is the case where three rodent studies would be conducted that separately addressed each of the components listed above. These study designs are described below. The day of insemination or detection of evidence of mating is considered Day 0 of gestation and the day of birth is considered postpartum and postnatal Day 0. Figure 8.1 presents line charts for the ICH Stage-Study Designs. 

TABLE 9.2. Tumor-bearing Animals in Control Groups from Rodent Studies... 

Schreck, R.W., Sekuterski, J.J. and Gross, K.B. (1986). Synchronized intratracheal aerosol generation for rodent studies. In Aerosols, Formation and Reactivity, Second International Aerosol Conference, Berlin. Pergamon Press, New York, pp. 37-51. 

In addition to rodent studies, regulatory guidelines for pharmaceuticals require that repeated dose safety studies of up to nine months (in the United States, six months elsewhere) in duration be conducted in a nonrodent species. The most commonly used nonrodent species is the dog, followed by the monkey and pig. Another nonrodent model used to a limited extent in systemic safety evaluation is the ferret. The major objectives of this chapter are (1) to discuss differences in rodent and nonrodent experimental design, (2) to examine the feasibility of using the dog, monkey, pig, and ferret in safety assessment testing, and (3) to identify the advantages and limitations associated with each species. 

Blood Collection. In rodent studies, large numbers of satellite animals (often close to the number used in the main study phase) are usually needed for pharmacokinetic blood sampling, whereas with most nonrodent species, blood samples can be collected from the main study animals without compromising their health status. 

Metabolism and pharmacokinetic studies have greater relevance when conducted in both sexes of young adult animals of the same species and strain used for other toxicity tests with the test substance. The number of animals used in metabolism and pharmacokinetic studies would be sufficient to reliably estimate population variability. This usually means a separate (but parallel) set of groups of animals in rodent studies. A single set of intravenous and oral dosing results from adult animals, when combined with some in vitro kinetic results, may provide an adequate data set for the design and interpretation of short-term, subchronic and chronic toxicity studies. 

We start by deciding the interval length (/,) we wish to examine within the study. The information we gain becomes more exact as the interval is shortened. But as interval length is decreased, the number of intervals increases and calculations become more cumbersome and less indicative of time-related trends because random fluctuations become more apparent. For a two-year or lifetime rodent study, an interval length of a month is commonly employed. Some fife table methods, such as the Kaplan-Meyer, have each new event (such as a death) define the start of a new interval. 

Treatment — As with all viral hemorrhagic fevers, supportive therapy must be given, dependent on the complications experienced by patients. Treatment would be intravenous ribavarin for 4 to 6 days. While no human studies to date verify the efficacy of this treatment, cell and rodent studies attest to its efficacy. An effective inactivated vaccine that can be administered in three doses is available. Protective antibodies appear before 14 days and last 1 year. Annual boosters must be given.3... 

The results of several acute- or intermediate-duration rodent studies indicate that the potential of di-w-octylphthalate exposure to cause adverse reproductive effects is very low. When male rats were exposed by gavage to 2,800 mg/kg/day of di- -octylphthalate for either 4 or 10 days, no testicular atrophy... 

The two models discussed below are derived from in vitro and in vivo rodent studies. It is important to keep in mind that these models were developed specifically to describe benzene metabolism, and as such, they may not fully consider the metabolism of phenol. PBPK models specific to phenol have yet to be developed. 

Species extrapolation. Extrapolation of this model from the rodent studies on which it is based to human exposure has not yet been done. 

High-low Dose Extrapolation. The Corley model was designed to facilitate extrapolations from high doses (similar to those used for chronic rodent studies) to low doses that humans may potentially be exposed to at home or in the workplace. 

Another, particularly direct, indication of irritability is the heightened startle response observed following the termination of nicotine infusion (Helton et al. 1993 Rasmussen et al. 2000). In addition, hyperalgesia, heightened responsiveness to painful or irritating stimuli, has been reported in several rodent studies of nicotine abstinence (Damaj et al. 2003 Grabns et al. 2005 Kota et al. 2007 Schmidt etal. 2001). 

Richter CA, Bimbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, Vandenbergh JG, Walser-Kuntz DR, vom Saal FS (2007) In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol 24 199-224... 

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