Differences between species

Species Tested. In addition to the variation in susceptibiUty to chemically induced toxicity among members within a given population, there may be marked differences between species with respect to the relative potency of a given material to produce toxic injury. These species differences may reflect variations in physiological and biochemical systems, differences in distribution and metaboHsm, and differences in uptake and excretory capacity. 

B. The Fa/Fb-Binding Subunit of RCI-Type Photosystems 1. Global Structure and Differences between Species... 

Most of the organic pollutants described in the present text act at relatively low concentrations because they, or their active metabolites, have high affinity for their sites of action. If there is interaction with more than a critical proportion of active sites, disturbances will be caused to cellular processes, which will eventually be manifest as overt toxic symptoms in the animal or plant. Differences between species or strains in the affinity of a toxic molecule for the site of action are a common reason for selective toxicity. 

In toxicity studies, acute toxicity tests are usually carried out in the rat, mouse, cat, and dog. Subacute toxicity studies for IM products are performed by giving SC injections to rats and IM injections to dogs. In IV studies the rat tail vein or a front leg is used. Deliberate overdosing usually washes out metabolism differences between species. In dogs it is common to give an IV dose five times that intended for humans. In rats this is increased to 10 times. 

Many nonlethal acute inhalation studies exist and are of generally good quality. These studies also suggest that there are few differences between species after acute exposure to phosgene and that the type and sequence of... 

The crucial point is that derivatization with a perfluoroalkyl group is required, in this instance, only to confer a sufficient polarity difference between species... 

With the advent of protein sequencing, also in the 1950s, attempts were made to study protein variation directly on the primary structure. However, the method was very expensive and time-consuming and could not be applied to population genetics. It remained confined to evolutionary study of differences between species (applied to molecular phylogenetics) and to the demonstration of sequence mutation in important heritable diseases. 

This exposure relationship is frequently more important in establishing human safety margins, as dose alone may be subject to a variety of differences between species such as absolute bioavailability, distribution, and excretion. This aspect, now commonly referred to as "toxicokinetics," has been outlined in an ICH guideline.6 This guideline specifies minimum requirements in terms of number of time points examined, number of animals per time point, and the requirements for calculation of various pharmacokinetic parameters such as Cmax, AUC. These will become important for comparison with human data as it becomes available later. 

Figure 7 shows the results for the corrected peak area plotted against injection time for the HC, LC, and non-HC and LC species called non-main species. The corrected peak area values are used because they compensate for velocity differences between species of different molecular size as they pass through the detector. These results demonstrate that the reduced CE-SDS method has a wide injection linearity range (5—40 s at —5kV) for the HC, LC, and non-main species. 

Much of the inter-species variation in pharmacokinetic properties can be explained as a consequence of body size (allometry). Consequently it is possible to scale pharmacokinetic parameters to the organism s individual anatomy, biochemistry and/or physiology in such a manner that differences between species are nuUified. Several excellent reviews on allometric scaling are available in the literature [2-7]. Allometric relationships can be described by an equation of the general form ... 

Free-ranging North American beaver. Castor canadensis, feed less on experimental aspen sticks that have been treated with extracts from predator excrement or urine. Odors from the sympatric coyote and river otter, and extirpated lynx, were most effective, while those from allopatric lion and extirpated wolf odor were less active. However, these response differences between species were small (Fig. 12.2 Engelhart and Muller-Schwarze 1995). 

As mentioned previously, the assessment of hazard and risk to humans from exposure to chemical substances is generally based on the extrapolation from data obtained in smdies with experimental animals. In the absence of comparative data in humans, a basic assumption for toxicological risk assessment is that effects observed in laboratory animals are relevant for humans, i.e., would also be expressed in humans. In assessing the risk to humans, an assessment factor is applied to take account of uncertainties in the differences in sensitivity to the test substance between the species, i.e., to account for interspecies variability (Section 5.3). If data are available from more than one species or strain, the hazard and risk assessment is generally based on the most susceptible of these except where data strongly indicate that a particular species is more similar to man than the others with respect to toxicokinetics and/or toxicodynamics. Two main aspects of toxicity, toxicokinetics and toxicodynamics, account for the namre and extent of differences between species in their sensitivity to xenobiotics this is addressed in detail in Chapter 5. 

In the context of assessment factors, it is important to distinguish between the two terms variability and uncertainty. Variability refers to observed differences attributable to true heterogeneity or diversity, i.e., inherent biological differences between species, strains, and individuals. Variability is the result of natural random processes and is usually not reducible by further measurement or study although it can be better characterized. Uncertainty relates to lack of knowledge about, e.g., models, parameters, constants, data, etc., and can sometimes be minimized, reduced, or eliminated if additional information is obtained (US-EPA 2003). 

S] is the aggregate scaling factor to account for known quantitative differences between species and between laboratory experimental conditions and the real world. The default value is 1, indicating that animals and humans are equivalent in these dimensions. 

Renwick et al. (2000) have performed an analysis of the need for an additional UF for infants and children. They considered that the proposal to introduce an additional 10-fold factor when exposure of infants and children is anticipated implies either age-related differences between species or differences within humans, which exceed those present in adults. Alternatively, the extra factor could be related to deficiencies of current testing methods or concerns over irreversibility in developing organ systems. They concluded that the available data did not provide a scientific rationale for an extra factor due to inadequacy of inter- and intraspecies UFs. Justification for the factor therefore must relate to the adequacy and sensitivity of current methods or concern about irreversible effects in the developing organism. They also pointed out that when adequate reproduction, multigeneration, or developmental studies are conducted, there will be no need for an additional 10-fold factor. 

It has been reported that embryotoxic or teratogenic effects of some compounds were detected in the New Zealand White rabbit, whereas there was no suspicion of such effects in the rat (2, 3). The origin of these differences between species has remained unelucidated in many cases. However, metabolism, systemic maternal exposure, maternal toxicity, fetal exposure, or placental transfer often explains the discrepancies. 

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