Biological variation

It is often postulated that extrapolation of biological data from animals to man must be viewed with extreme caution because of man s biological uniqueness. 

This highhghts the importance of uncertainties in interspecies extrapolation in cases where the expression of chemical toxicity is related to its metabolism, and it is widely believed that interspecies differences in metabolism of xenobiotics is usually the most significant explanatory factor for observed interspecies differences (Davidson et al. 1986, Voisin et al. 1990, Calabrese et al. 1992). 

In addition to the toxicokinetic and toxicodynamic differences mentioned above, other aspects of differences between experimental animals and humans include different types of organs and tissues, differences in digestion, and differences in the stmcture of the upper respiratory tract. Furthermore, animal studies are performed in homogenous groups of animals, but the results have to be apphed for the protection of all individuals in a heterogeneous population of humans. In consequence of this, interspecies variation must also be expected. 

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. 

2 Adjustment for Differences in Body Size Allometry/Scaling 

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Cell separation techniques that use an inward flow component are referred to as countercurrent separation techniques. The concept of countercurrent separation is compHcated by biological variations of all parameters in equation 4. 

Fraser has extensively discussed this relationship between laboratory work and clinical needs (Fraser and Hyltoft Peterson 1993) and has recently addressed the role of documented analytical quality as derived from measurements of RMs (Fraser and Hyltoft Peterson 1999). Among the concepts proposed by Fraser and his colleagues, it is suggested that analytical imprecision should be <0.50 CVi and bias should be <0.25 (CVi + where CVj is the within-subject biological variation (i.e. changes from day to... 

One common application of liquid-liquid extraction is the removal and recovery of phenol and compounds of phenol from wastewaters. Although phenol can be removed by biological treatment, only limited levels can be treated biologically. Variations in phenol concentration are also a problem with biological treatment, since the biological processes take time to adjust to the variations. 

Thiericke, R. and Rohr, J. (1993) Biological variation of microbial metabolites by precursor-directed biosynthesis. Natural Product Reports, 10 (3), 265-289. 

Animal model results are indicative of the potential toxicity, but the mode of administration, size of the dose, and duration of exposure may set up different responses from those we can expect in human situations. Biological variation, side effects of treatment, and the workup may introduce artifacts or changes not directly related to the experiment, or may mask the changes sought as the result of the treatment. Some degree of disagreement and uncertainty in interpretation must be expected (even for studies submitted to statistical evaluation), which can be resolved only with further discussion and experimentation. 

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. 

Random error is the divergence, due to chance alone, of an observation on a sample from the true population value, leading to lack of precision in the measurement of an association. There are three major sources of random error individual/biological variation, sampling error, and measurement error. Random error can be minimized but can never be completely eliminated since only a sample of the population can be studied, individual variation always occurs, and no measurement is perfectly accurate. 

As can be seen from these two examples, an achievement of statistical significance very much rehes on the number of animals included in the various dose groups. If statistical significance is not achieved for a specific biologically relevant endpoint or parameter, the effect should be considered as being adverse if it is plausible that the effect is not related to biological variation and thus... 

This section gives a short introduction regarding the biological variation between mammalian species (Section 5.3.1) as a basis for the subsequent section on aUometric scaling (Section 5.3.2). Then a number of analyses performed regarding the validity of the default assessment factor of 10 are reviewed (Sections 5.3.3 and 5.3.4). Finally, the key issues are summarized and our recommendations are presented (Section 5.3.5). 

The metabolic and clinical condition of the patient also plays a role The individual with good kidney and liver function will respond quite differently to a drug than the patient who is not able to detoxify or excrete the compound. The user of laboratory data must be aware of the possible occurrence of drug-mediated enzyme induction, biological variations in the rate of clearance and storage in depot areas (B24), and the genetic factors that play a role in the toxicity of a drug (L2). 

There are a number of articles in which attempts have been made to define the mechanisms of specific laboratory interferences, the role of sample quality on the analysis, and the effect of biological variation in the reported values (C2, C3, C4, L6, S8, S30, Wll). The clinical chemist... 

The second level used to define the requirement for analytical quality is often cited as the Cotlove model [2], defining acceptable analytical imprecision as less than 0.5 times the within-subject biological variation measured as the coefficient of variation... 

Such effects may be confused or obscured by normal biological variation, as they are typically only 30% to 60% above the control. Furthermore, if the background level of tumor incidence (or other effect being measured) is low, it may be impossible to assess hormesis. 

Refsgaard, H.H.F., Brockhoff, P.B., and Jensen, B. 1998. Biological variation of lipid constituents and distribution of tocopherols and astaxanthin farmed Atlantic salmon (Salmo salar). J. Agric. Food Chem. 46 808-812. 

In addition to SES, race, and ethnicity, biologic variation between and within people must be considered in sampling populations because at a... 

Intra-individual variability Biological variation within people. Interindividual variability Biological variation between people. 

In the UK the Joint Food Science and Safety Group of the Department of Health and the Ministry of Agriculture, Fisheries and Food have published the results of many analyses for chemical contaminants in food carried out under their Food Surveillance Programme. In many cases the raw data from these surveys are available for analysis. Table 2.1 lists the results of analyses for lead in some samples of cow, sheep and pig kidney obtained in Scotland and England.5 There are clear differences between species and some evidence of differences between sampling locations. What is not clear is the extent to which the variability observed is due to real and consistent differences between species and location or to normal biological variation. 

Total PCDDs and PCDFs were usually used for comparison, however, it should be noted that different studies used different standards to calculate total PCDDs/PCDFs. The eggs of double-crested cormorants that were collected from Mandarte Island, and Crofton and Mitlenatch Islands, in the Strait of Georgia, in British Columbia, Canada, between 1973 and 1998 have been analyzed for PCDDs and PCDFs (Harris et al., 2003). The study showed that the levels of total PCDDs and PCDFs in 1998 were lower than those from 1973 to 1989 (Table 8.9). In another study, the PCDDs/PCDFs levels in white-tailed sea eagle livers were analyzed (Kannan et al., 2003). It showed that no significant difference in the total PCDDs/PCDFs in adult females that were collected from 1985 to 1995 was observed. However, this observation was confounded by small sample sizes and associated inherent biological variations. 

Keywords Traceability Laboratory medicine Biological variation Analytical bias Quality assurance Standardization Reference measurement system Joint Committee on Traceability for Laboratory Medicine... 

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