Susceptibility, interspecies variations

We have developed a quantitative structure-activity model for the variations in potency among the nitrosamines and, more recently, a related model for the variation in target organ for a smaller set of nitrosamines. We are currently developing a model for interspecies variation in susceptibility toward carcinogenic nitrosamines. The model for organ selectivity requires terms for the parent nitrosamine as well as for the hypothesized metabolites while the model for potency variations contains terms only for the unmetabolized parent compound. 

Interspecies Variations in Susceptibility. An Important assumption in the development of both the structure-potency model (eq, 1) and the structure-target-organ model (eq, 2) was that all of the test compounds were administered at equal daily... 

It does suggest, however, that our original assumptions concerning d were at least reasonable. In addition, the dose-depen-dent model can be manipulated to examine - in a general sense -some aspects of interspecies variations in susceptibility to nitrosamine carcinogenesis. 

UFi accounts for the interspecies variation in susceptibility. The default value is 10 when correction for differences in body size between humans and experimental animals is based on the body weight. 

As described in a highly referenced document (NRC, 1983), important components of this process include hazard identification, assessment of exposure and dose-response relationships, and characterization of the risk. Uncertainty factors are built into the risk assessment process to account for variations in individual susceptibility, extrapolation of data from studies in laboratory animals to humans (i.e. interspecies variation in toxicokinetics), and extrapolation from high-dose to low-dose exposures. In the case of the association between exposure to chemicals and drugs and autoimmunity or autoimmune diseases, much of the information needed to evaluate risk in the context of the traditional United States National Research Council paradigm is not available. The following represents a discussion of issues in chemical-induced autoimmunity relevant to the use of existing data and data needs in risk assessment. 

Animal-to-human extrapolations of the toxicity of creosote are complicated by the inherent chemical variety of these substances. Creosotes are complex mixtures of variable composition and the individual components are likely to show interspecies variation in toxicity. Only one study was located that treated more than one species of animal with the same sample of creosote (Miyazato et al. 1981), and although this study suggested that mice were more susceptible to the acute effects of beechwood creosote than rats, the differential susceptibility observed with this particular sample cannot be applied to creosotes of different composition. In general, the adverse effects observed in animals are similar to those reported for humans with cancer being the most serious, but it is not possible at present to assess whether the doses required to produce adverse effects in animal systems are similar to those required to produce similar effects in humans. 

Animal and human susceptibility to carbon tetrachloride hepatotoxicity is dependent on many different factors. There is substantial interspecies variation in carbon tetrachloride induced hepatotoxicity in animals due to differences in metabolic pathways among species. Based on animal models, hepatotoxicity in humans is most likely mediated from the trichloromethyl radical formed from the metabohsm of carbon tetrachloride by hepatic cytochrome p 450 2E1 Animal studies suggest differential hepatotoxicity based upon the animal s age and gender, with greater toxicity demonstrated in adult rats compared to newborns, and males compared with females. Cytochrome p-450 enzyme systems are present in the human fetus suggesting a potential for in utero fiver toxicity. Human gender differences in the metabolism of carbon tetrachloride have not been demonstrated despite potential sex steroid influences on the cytochrome p-450 system. ... 

Uncertainty factors Interspecies 3—The monkey was more susceptible than the rat the lowest concentration in a range was chosen (70 ppm) humans and monkeys showed changes in the visual evoked response at similar concentrations the monkey is a good model for the human. The concentration inducing central nervous system depression does not vary greatly among mammalian species. Intraspecies 3—Individual variation in susceptibility to central nervous system depressants such as anesthetics varies no more than 2-fold. 

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