10-Fold interindividual

Fig. 1. Frequency distribution of the area under the plasma concentration versus time curve (AUC) of nifedipine in plasma after oral administration of 20 mg nifedipine to 130 healthy subjects (from [5]). There is 10-fold interindividual variability in AUC in this...

There are at least two SNPs (boxed in Figure 9.5) in the dbSNP track that are present in the 3 -UTR and could have functional significance. Since the coding polymorphisms in CAR are rare (Table 9.3), CAR hepatic expression shows 200-fold interindividual variation the variation in CAR may be due to either sequence variations 5 or 3 to the CAR coding region, or may be due to nucleotide variation in transcription factors regulating CAR. 

The level of adducts formed in human hepatocytes was higher than in HepG2 cells and showed significant (20-fold) interindividual variation, for example, after treatment with 1 pM PhlP for 24 h, the level of adducts were found between 332 and 6892 adducts/10 liases in different subjects (n=6). HepG2 cells, in comparison, gave 92 + 5 adducts/10 bases under the same conditions [92]. Differences in the levels of adducts obtained between cell types can principally be attributed to levels of PhlP activation by enzymes such as GYP 1A2. It has been reported that HepG2 cells showed only 10-20% of the cytochrome P-450 activity of the human hepatocytes [94]. Considering the differences in individual human exposure, rates of metabolism, and DNA repair, the difference in human cancer risk for HCAs could be more than 1000-fold [69]. 

The metabolism of DMN has also been studied in cultured human bronchi and colon. These tissues may be exposed to DMN via inhalation of tobacco smoke or polluted air or by endogenous formation in the colon. Human bronchi metabolized [ C]DMN to C02- Binding to protein and DNA was observed, with higher levels of binding to protein. Bronchial DNA was methylated at 0-6 and N-7 (777, 178). Similar results were obtained in colon. A 50-fold interindividual variation was found in the binding of DMN to colonic DNA N-7 and... 

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. 

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... 

The approach proposed by Renwick (1991, 1993) is also based on the 100-fold factor. It attempts to give a scientihc basis to the default values of 10 for the interspecies and 10 for the intraspecies (interindividual human) differences. Renwick also proposed a division of each of these UEs into sub-factors to allow for separate evaluations of differences in toxicokinetics and toxicodynamics. The advantage of such a subdivision is that components of these UEs can be addressed where data are available for example, if available data show similar toxicokinetics of a given chemical in experimental animals and humans, then only an interspecies extrapolation factor would be needed to account for differences in toxicodynamics. Renwick examined the relative magnitude of toxicoki-netic and toxicodynamic variations between and within species in detail. He found that toxicokinetic differences were generally greater than toxicodynamic differences resulting in the proposal that the 10-fold factors (for inter- and intraspecies variation) should, by default, be subdivided into factors of 4 for toxicokinetics and 2.5 for toxicodynamics. It should be noted that the proposed default values were derived from limited data. 

Hattis et al. (1987) examined the variability in key pharmacokinetic parameters (elimination half-lives (Ty ), area under the curve (AUC), and peak concentration (C ax) in blood) in healthy adults based on 101 data sets for 49 specific chemicals (mostly drugs). For the median chemical, a 10-fold difference in these parameters would correspond to 7-9 standard deviations in populations of normal healthy adults. For one relatively lipophilic chemical, a 10-fold difference would correspond to only about 2.5 standard deviations in the population. The authors remarked that the parameters studied are only components of the overall susceptibility to toxic substances and did not include contributions from variability in exposure- and response-determining parameters. The study also implicitly excluded most human interindividual variability from age and diseases. When these other sources of variability are included, it is likely that a 10-fold difference will correspond to fewer standard deviations in the overall population and thus a greater number of people at risk of toxicity. 

Reanalysis of the data of Hattis et al. (1987) showed that the variation between individuals for the elimination half-life was quite small (Schaddelee 1997, as cited in Vermeire et al. 1999, 2001). Defining the interindividual factor as the ratio of the P50 (50th percentile) and P05 (5th percentile) resulted in a factor of 1.4. It was emphasized that although it appeared from this analysis that a 10-fold factor would be sufficient for pharmacokinetic variation, the real median to sensitive human variability is underestimated because variation also exists in pharmacodynamics and only data of healthy volunteers were available. 

Gronlund (1992) has investigated methods used for quantitative risk assessment of non-genotoxic substances, with special regard to the selection of assessment factors. Gronlund found that the 10-fold factor suggested for interindividual variability probably protects a majority but not all of the population. 

Renwick (1991, 1993) analyzed interindividual differences of healthy volunteers by comparing the maximum and mean values of pharmacokinetic parameters (7 substances) and pharmacodynamic parameters (6 substances). The data indicated that toxicokinetic differences were slightly greater than toxicodynamic differences. With one exception, the ratios between the maximum and mean value for a substance s kinetic parameter ranged from 1.8 to 4.2 with most values between 3 and 4, and it was concluded that a factor of 3-4 would be sufficient to consider toxicokinetic differences for 99% of the healthy, adult population and for 80% of the substances. The ratios between the maximum and mean value for a substance s dynamic parameter ranged from 1.5 to 6.9 with most values between 1.7 and 2.7. Based on the analyses, Renwick proposed to subdivide the interindividual factor of 10 into a factor of 4 for pharmacokinetic differences and a factor of 2.5 for pharmacodynamic differences. The aim of the subdivision of the 10-fold factor was to allow the incorporation of suitable compound-specific data for one particular aspect of uncertainty. 

According to US-EPA (1993), a 10-fold factor is generally used, in addition to the assessments factors for interspecies and interindividual differences, when extrapolating data from less than chronic results on experimental animals when there are no useful long-term human data. This factor is intended to account for the uncertainty involved in extrapolating from less than chronic NOAELs to chronic NOAELs and is referenced as lOS. ... 

A variable metabolic response to isoflavones has been shown for subjects following consumption of soy flour urinary excretion concentrations of genistein, daidzein, equol, and O-DMA were increased 8-, 4-, 45-, and 66-fold, respectively, compared to baseline. Considerable interindividual variation in metabolic response was reported with the peak levels of equol showing the most variation. ... 

Adipose tissue poses additional calibration differences for microdialysis sampling devices. The thickness of the tissue (e.g., lean versus obese individuals) and thus the capillary density will affect interindividual microdialysis sampling recovery values. This has been shown by Lutgers et al., who demonstrated decreases in glucose recovery of up to 50% between human volunteers with a skin fold thickness of 20 versus 45 mm.65 This points to how microdialysis sampling recovery is dependent upon analyte supply since glucose will be supplied better to the microdialysis probe in lean individuals with a higher density of capillaries per unit tissue than obese subjects with a lower density of capillaries and thus an increased mass transfer resistance to the probe. Additional reports have also shown less interindividual differences between microdialysis probes implanted in the forearm versus in the subcutaneous tissue.66... 

The NOAEL or benchmark dose/concentration is selected, then, generally to be at or below the threshold in animals uncertainty factors are then applied to estimate the subthreshold in sensitive human populations, with a 10-fold default factor addressing interspecies differences (i.e. the variation in response between animals and a representative healthy human population) and another 10-fold factor accounting for interindividual variability in humans (the variation in response between a representative healthy human population and sensitive subgroups). While additional factors are sometimes applied to account for deficiencies of the database, the 100-fold default value is common. 

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