Extrapolation to the Human Situation

The few available studies of the morphological consequences of low-level lead exposure indicate that young rats, exposed to lead levels insufficient to produce overt signs of clinical toxicity, show 

Results of Network Analysis of 30-d Control 2% Lead-Exposed, and 0.5% Lead-Exposed Dendritic Networks 

Unlike animal models of clinical lead poisoning, the validity of experimental models of low-level lead exposure obviously cannot be confirmed by direct comparison wdth human material. The relevance of such models to low-level lead exposure in humans must therefore be assessed by considering their comparability in terms of the severity, duration, and timing of the insult. 

Interspecies equation of the timing of exogenous influences on CNS development is fraught with difficulties, since the events involved in brain maturation occur at different times in relation to birth in different species. It is necessary, therefore, to consider the timing of the insult in relation to the stages of brain maturation, rather than its relation to birth. 

The degree of brain maturation in the newborn rat is comparable to that achieved in the mid-term human fetus. The 7-month-old human infant is probably equivalent, at least in terms of maturation of neuronal connectivity, to a 21-d rat pup, with the major period of dendritic elaboration virtually complete in both the cerebral and cerebellar cortices. Hence, the experimental models of low-level lead exposure used to date, in which rat pups were maintained on a leaded diet firom 

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In the past the results of toxicology studies were interpreted and extrapolated to the human situation on the basis of the dose/kg or dose/m. However, it has long been recognized that measuring the plasma concentration of the compound and its metabolites often provides a better indication of exposure, and therefore this has become mandatory. The area under the plasma concentration-time curve (AUC) and... 

Risk assessment. This model successfully described the differences in disposition of 2-butoxy-ethanol, based on urinary profdes of metabolites, in various exposure routes by taking into account the differences in absorption rate and by incorporating a minor pathway for metabolism (glucuronidation) by skin (Shyr et al. 1993). The model was reasonably successful in predicting the experimental rat data produced by Johanson et al. (1986a). The value of the model lies in the ability to extrapolate to the human situation from the routes of exposure likely to be used in experimental assays. 

In brief, it is clear from the data presented in this chapter that major species differences exist in the relative enrichment and distribution of a given NPY receptor-type. For example, while the mouse and rat brain cortices are enriched in Y1 receptor binding sites these same areas are mostly devoid of this class of sites in the monkey and human brain. The guinea-pig brain is particular enriched with the Y1 type. Hence, at least in regard to the two best studied classes ofNPY receptors, the Y1 and Y2 types, great care must be taken when extrapolating to the human situation on the basis of results obtained in other species. It remains to be established whether similar consensus apply to Y3 and the newly characterized PP1/Y4, Y5 and Y6 receptor types, only very limited information currendy being available on their expression in the mammalian brain. In any case it would appear that the use of human brain tissues is critical to establish clearly the relevance of data obtained in other species. Moreover,... 

In animal experiments exposures can be carefully controlled, and dose-response curves can be formally estimated. Extrapolating such information to the human situation is often done for regulatory purposes. There are several models for estimating a lifetime cancer risk in humans based on extrapolation from animal data. These models, however, are premised on empirically unverified assumptions that limit their usefulness for quantitative purposes. While quantitative cancer risk assessment is widely used, it is by no means universally accepted. Using different models, one can arrive at estimates of potential cancer incidence in humans that vary by several orders of magnitude for a given level of exposure. Such variations make it rather difficult to place confidence intervals around benefits estimations for regulatory purposes. Furthermore, low dose risk estimation methods have not been developed for chronic health effects other than cancer. The... 

Extrapolation of data from studies in experimental animals to the human situation involves two steps a first step is to adjust the dose levels applied in the experimental animal studies to human equivalent dose levels, i.e., a correction for differences in body size between laboratory animals and humans. A second step involves the application of an assessment factor to compensate for uncertainties inherent in toxicity data as well as the mterspecies variation in biological susceptibility. These two steps are addressed in the following sections. 

In the following text, various studies will be described, which attempt to establish a scientific rationale for the selection of the interspecies assessment factor. Based on these studies, it can be concluded that a species-specific default factor based on differences in caloric requirement (see Table 5.4) should be used for interspecies extrapolation regarding metabolic size. The remaining interspecies differences should preferentially be described probabilistically, or a deterministic default factor of 2.5 could be used for extrapolation of data from rat studies to the human situation. 

The Monographs represent the first step in carcinogenic risk assessment, which involves examination of all relevant information in order to assess the strength of the available evidence that certain exposures could alter the incidence of cancer in humans. The second step is quantitative risk estimation. Detailed, quantitative evaluations of epidemiological data may be made in the Monographs, but without extrapolation beyond the range of the data available. Quantitative extrapolation from experimental data to the human situation is not undertaken. 

Whenever possible, human data should be used/considered in the risk assessment. However, since risk assessments generally rely on test animal data, comparative studies into the toxicokinetics and toxicodynamics of animals and humans are important for extrapolating test animal data to the human situation. Moreover, in the case of children s risk assessment, it is important to define the comparative adult/child toxicokinetics and toxicodynamics at different life stages. 

Neuronal cultures derived from human stem cells can possibly serve as renewable source of normal (non-transformed) cells with the capacity to differentiate into any cell type present in the nervous system. The major advantage of human cell types-based in vitro models is that the results do not require extrapolation from animal data to the human situation. The detailed characterization of human stem/progenitor cell-based assays for neurodevelop-mental toxicity testing is described in Chap. 16 of this book by E. Eritsche. 

The limitation of many in vitro studies is the extrapolation of data from experimental models to the human situation. A major obstacle is the use of concentrations of carcinogens or protective compounds that are not phy siologically relevant to normal exposure levels in humans and hence offer little or no insight regarding dose-response effects and interactions [106]. This study, using AMS, demonstrated the use of PhiP concentrations of 100 pM, which is lower than PhiP exposure from a normal diet. The formation of PhIP-DNA adducts was also dosedependent. 

When extrapolating from animal experiments to the human situation one has to be very careful if the modes of application are different. Teratological experiments in which mercury had been given by the i.p. or i.v. route are, therefore, not comparable to mercury poisoning of the human fetus. Feeding experiments, however, are more suitable and I will only refer to such studies. Childs (1973) has fed tuna fish containing different amounts of methylmercury to pregnant mice and has determined the mercury concentrations in the embryos. He found a positive correlation between maternal uptake and embryonic content of this heavy metal. 

In some species, like man, guinea pig and pig, lipoproteins of the LDL type, in which apolipoprotein B predominates, account for more than 50% of the total substances of density < 1.21 gml". They are the LDL mammals. In the vast majority of mammals, however, HDL are the predominant class and may account for up to 80% of plasma substances of density < 1.21 g ml. Herbivorous species, with the exception of guinea pigs, camels and rhinos, and carnivores are HDL mammals. It is worth noting that although rats are most frequently the animal of choice for the study of lipid biochemistry in the research laboratory, their lipoprotein pattern is of the HDL type and very different from that of man. Caution needs to be exercised in extrapolating results on experimental animals to the human situation. 

To appreciate the regulatory problems this approach leads to, it is important to understand that risk assessment was developed as a tool for carrying out risk management, rather than a scientific process for understanding risk. Thus, both the selection of the data to be used and the way these data are extrapolated to the usual human exposure situation, reflect both scientific and policy considerations. As a result, risk assessment results do not represent the best scientific estimates of risk, estimates that are subject to scientific consensus, but rather prudent values that incorporate margins of safety. These margins of safety are included to increase the likelihood that regulations based on these risk assessments will successfully protect the public and the environment. 

In risk assessment it is necessary to do extensive extrapolations. In human toxicology, we must extrapolate to man from experiments done on animals such as rats, guinea pigs, and hamsters. Even experiments performed on cells and bacteria are used in the assessment, which makes extrapolation even more extensive. In ecotoxicology we must extrapolate from one or few organisms, such as the most popular test organisms (e.g., the crayfish Daph-nia magna, the earthworm Eisenia fetida, or the collembolan Folsomia Candida) to all species in the environment. We must also extrapolate from laboratory experiments to the field situation. 

A more philosophical problem arises with the question of extrapolating from animal studies on neurodegeneration and repair to the clinical situation. Once again, there is no inherent reason to doubt that similar mechanistic events exist in rats (or mice) to those in humans. Nevertheless, given the fact that the respective lifespans... 

As noted by Rodgman and Green (3300), Gold et al., colleagues of Ames, as recently as 1998 questioned the extrapolation of laboratory animal tumorigenesis data generated by the use of a maximum tolerated dose (MTD) to a human situation. They stated (1318a) ... 

Mai ls In the mouse system we have found that ILIO is not required for down-regulation by helminths. This can t be extrapolated to prejudge the human situation. Different cells make ILIO in humans and mice, and there may also be a time phenomenon the mouse models are abbreviated, while ILIO may have a role in the long-term homeostatic context rather than in a more compressed experimental time frame. 

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