Interindividual differences

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

Evans WE, Johnson JA Pharmacogenomics the inherited basis for interindividual differences in drug response. Anna Rev Genomics Hum Genet 2001 2 9. 

Lipscomb JC, Garrett CM, Snawder JE. 1997. Cytochrome P-45 0-dependent metabolism of trichloroethylene Interindividual differences in humans. Toxicol Appl Pharmacol 142 311-318. 

The importance of adenosine deaminase in the duration and intensity of sleep in humans has been noted recently (Retey et al. 2005). Animal studies suggest that sleep needs are genetically controlled, and this also seems to apply in humans. Probably, a genetic variant of adenosine deaminase, which is associated with the reduced metabolism of adenosine to inosine, specifically enhances deep sleep and slow wave activity during sleep. Thus low activity of the catabolic enzyme for adenosine results in elevated adenosine, and deep sleep. In contrast, insomnia patients could have a distinct polymorphism of more active adenosine deaminase resulting in less adenosine accumulation, insomnia, and a low threshold for anxiety. This could also explain interindividual differences in anxiety symptoms after caffeine intake in healthy volunteers. This could affect the EEG during sleep and wakefulness in a non-state-specific manner. 

Cashman JR, Zhang J. Interindividual differences of human flavin-containing monooxygenase 3 genetic polymorphisms and functional variation. Drug Metab Dispos 2002 30(10) 1043-1052. 

Various organic constituents of blood have been found in normal individuals in the ranges of concentration shown in Table 7.16,2432 There are many items in the list for which there is a 3- or 4-fold variation, and about a dozen for which the variation is of the order of 10-fold or more. These data strongly suggest that marked interindividual differences exist, but they do not offer proof except where repeated samples have been analyzed from the same individuals. 

In experiments carried on in the author s laboratory several years ago, the B vitamin content of milks from individual cows and from individual human mothers was determined.63 So far as this study is concerned, involving as it did only B vitamins, the intra-individual variation (that is, from day to day) appeared to be greater than interindividual differences. The number of human cases studied was not sufficient to be the basis of any sound conclusion on this point. 

In view of the lack of satisfactory data, the evidence for substantial inter-individual differences in milk composition is limited, and satisfactory conclusions must await further study of both inter-individual and intra-individual differences. The available data suggest that interindividual differences may be substantial and important in the case of ascorbic acid, folic acid, and vitamin B12. 

From the stand-point of our discussion the conclusion is clear Wide inter-individual differences exist with respect to this type of enzyme as it appears in the blood. On the basis of observations cited above, it is apparent that these interindividual differences are significant in relation to metabolism and disease. 

Just what enzyme or enzymes are involved in these differences is not obvious, but it is clear that marked interindividual differences (presumably genetic in origin) exist with respect to them. Here we see also a distinct gradation in the utilization figures which seem to bear out the principle of genetic gradients referred to earlier (p. 13). 

On the basis of this concept, one might expect a poison to be relatively uniform in its toxic effect on a series of intact animals because, in the different animals, many different tissues and organs would be involved and the chance exists that the resistance of one tissue might be compensated for by the susceptibility of another. Since from our previous discussions we realize that every individual animal is made up of a coordinated set of organs and tissues, each distinctive (quantitatively) in size, composition, and enzymic make-up, we should expect the greatest interindividual differences to be observed when single tissues from different animals are tested in parallel. This exemplifies the principle which appears to be an important one for our discussions. We expect to find the most striking evidences for biochemical individuality when we look at details, rather than at crude summations. 

One might suppose on the basis of the amount of attention PTC has received that it is quite a unique substance in its ability to elicit different responses from different individuals. Actually this is not the case at all since wide interindividual differences in taste threshold and taste reactions can be observed with almost anything that can be tasted. Hundred-fold variations in taste thresholds are very common (even when small groups are studied) with respect to substances like sodium or potassium chlorides or hydrochloric acid.41 Saccharine, quinine, cascara, and mannose are among the substances, in addition to creatine mentioned above, for which individuals are known to show highly diverse taste reactions.42 Richter found some children who could not taste 20 per cent sugar solutions.43... 

Before discussing the broader aspects of nutrition and the possibility of its application to the solution of some of the problems that arise because of biochemical individuality, we will consider, in sequence, several nutritional items for which the evidence of interindividual differences seems particularly worthy of attention. Rather than attempt the discussion of every known nutritional item from this standpoint, we will exercise some selection. The omission of a particular item from our discussion, however, should not carry the implication that inter-individual differences with respect to this item do not exist. 

Sensitivity selection of panelists as a function of their individual thresholds of perception on 5 pure products. Interindividual differences ranging between 1 and 1000 are accepted, as it really occurs. 

Yamanaka H, Nakajima M, Fukami T, Sakai H, Nakamura A, Katoh M, Takamiya M, Aoki Y, Yokoi T (2005b) CYP2A6 AND CYP2B6 are involved in nornicotine formation from nicotine in humans interindividual differences in these contributions. Drug Metab Dispos 33 1811-1818... 

Pharmacogenomics is the study of the inherited basis of interindividual differences in drug response. One approach is to search for genetic variants that are associated with severe adverse effects, which in turn can be used to screen for individuals who should not receive the drug in question or should receive an adjusted dose of the dmg. Another approach is to identify markers that predict dmg efficacy (2-4). 

Synthetic musks have been detected in human tissues (Table 8) due to their lipophilic nature and their low biodegradability. The occurrence of these fragrance-related chemicals is subjected to a variable pattern with substantial interindividual differences, opposed to other environmental contaminants such as polychlorinated biphenyls (PCBs) or pesticides [165]. 

The evaluation of a dose-effect relationship within a group of human subjects is compounded by interindividual differences in sensitivity. To account for the biological variation, measurements have to be carried out on a representative sample and the results averaged. Thus, recommended therapeutic doses will be appropriate for the majority of patients, but not necessarily for each individual. 

Data on the toxicokinetics of a substance can be very useful in the interpretation of toxicological findings, and may replace the use of some default extrapolation factors used in route-to-route (Section 5.5) or interspecies extrapolations (Section 5.3). In addition, interindividual differences in sensitivity to toxicants may be identified on the basis of toxicokinetic data, thereby making it possible to make the risk assessment more comprehensive by including sensitive subpopulations (Section 5.4). In conjunction with information on the relationship between concentration-dose at the target site and the toxic effect, toxicokinetic information may be an important tool for extrapolation from high to low dose effects. 

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