Chemicals rodents responding

In order to extrapolate laboratory animal results to humans, an interspecies dose conversion must be performed. Animals such as rodents have different physical dimensions, rates of intake (ingestion or inhalation), and lifespans from humans, and therefore are expected to respond differently to a specified dose level of any chemical. Estimation of equivalent human doses is usually performed by scaling laboratory doses according to observable species differences. Unfortunately, detailed quantitative data on the comparative pharmacokinetics of animals and humans are nonexistent, so that scaling methods remain approximate. In carcinogenic risk extrapolation, it is commonly assumed that the rate of response for mammals is proportional to internal surface area... 

A second approach to the problem of toxic potency measurement has been to expose laboratory animals, usually rodents, to the smoke from the combustion of small samples of a burning material. Measurement of their response to the smoke leads to one of several biological endpoints, such as the LC50 (the concentration of smoke lethal to 50% of the test animals). In this approach, the animals respond to all the toxicants that are present in the smoke. It presumes that rodent mortality can be related to human mortality or, more simplistically, that the relative toxicity of the smokes will be similar in humans and rodents. However, since the relative contributions of the individual toxic chemicals in the smoke are not determined, a quantitative relationship between man and rodent is impossible using this approach. 

As with many macrosmatic mammals, rodents have two separate chemosensory systems, the main olfactory system (MOS) and accessory olfactory system (AOS), which respond to social odors. Importantly, these sensory systems differ not only in their peripheral morphology and central projections, but also in the types of chemosignals that they process (Meredith 1991). Sensory neurons of the MOS, which are located in the main olfactory epithelium and project to the main olfactory bulbs, process volatile chemicals and can detect odors at a distance. In contrast, sensory neurons of the AOS, which are located in the vomeronasal organs (VNO) and project to the accessory olfactory bulbs, primarily process large, non-volatile chemicals and require contact for stimulation (Meredith 1991). 

FIGURE 8.4 The Bronson model of priming pheromone actions in rodents. Chemical signaling between males and females constitutes a feedback mechanism that results in accelerated maturation and reproduction. This, in turn, permits the mice to adjust their reproduction and population size quickly to respond to environmental conditions such as sudden food abundance at harvest time. FSH, follicle-stimulating hormone LH, luteinizing hormone PRL, prolactin. Stimulation and inhibition are marked by - - and —, respectively. (From Bronson and Coquelin, 1980.)... 

Dose-response data based largely on animal studies. It is noteworthy that rodent studies now used to predict the dose-response relationship in humans were never intended for that purpose (Barr, 1988). These studies were designed for purposes of hazard identification (see Section 3.1.4.1.2) and were not intended to be the basis for estimating human responses at low doses (Paustenbach, 1995). For example, there usually are significant differences between animals and humans with respect to the rate at which chemicals are metabolized, distributed, and excreted, and these are not taken into account when animal tests are designed. Also, animal tissues will frequently respond differently to toxicants than human tissue. 

During the first half of the century, there was virtually an exclusive reliance on animal testing as the primary model for drug discovery and development. New chemical entities were administered to rodents in the primary screen assay, and the appropriate responses were monitored for indications of therapeutic potential. Compounds meeting the appropriate potency and efficacy criteria were promoted to more diverse and sophisticated animal models to characterize their pharmacological profile. The responses that were monitored included blood pressure (hypotensives), latency to respond to painful stimuli (analgesics), attenuation of seizure propensity (antiepileptics) and other responses that were intuitively and pharmacologically valid indicators of medicinal potential or toxicity. Some of these methods were semiautomated and quite sophisticated for their time, particularly for cardiovascular indications [1]. 

Although activation of the AHR by DLCs is a key event, mechanistic data indicate that AHR-mediated responses are not well conserved across species, with lower sensitivity in humans. A TEF value for a DLC based on rodent data may overestimate the potency of a DLC in humans, and this has not been considered in the current risk assessment of DLCs. Thus, the current TEF-Toxic Equivalency Quotient scheme tends to compound the conservative estimates of risk that exist within standard risk assessment approaches. Moreover mechanistic differences will now be considered by US EPA in the risk assessment of chemical carcinogens. The mechanistic data currently available for receptor-mediated DLCs and PPs clearly indicate that humans respond differently to these two classes of rodent carcinogens, and these data will need to be incorporated into cancer risk assessments for these chemicals. Full appreciation of the species differences in these receptor mechanisms will require continued development and refinement of models such as primary... 

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