Individual variations animal studies

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-... 

In the case of noncarcinogenic substances, there exists a threshold this is an exposure with a dose below which there would not be adverse effect on the population that is exposed. This is the reference dose (RfD), and it is defined as the daily exposure of a human population without appreciable effects during a lifetime. The RfD value is calculated by dividing the no observed effect level (NOEL) by uncertainty factors. When NOEL is unknown, the lowest observed effect level (LOEL) is used. NOEL and LOEL are usually obtained in animal studies. The main uncertainty factor, usually tenfold, used to calculate the RfD are the following the variations in interspecies (from animal test to human), presence of sensitive individuals (child and old people), extrapolation from subchronic to chronic, and the use of LOEL instead of NOEL. Noncancer risk is assessed through the comparison of the dose exposed calculated in the exposure assessment and the RfD. The quotient between both, called in some studies as hazard quotient, is commonly calculated (Eq. 2). According to this equation, population with quotient >1 will be at risk to develop some specific effect related to the contaminant of concern. 

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. 

Threshold limit values (TLVs) refer to airborne concentrations of substances and represent conditions under which it is believed that nearly all workers may be repeatedly exposed day after day without adverse effect. Because of wide variation in individual susceptibility, a small percentage of workers may experience discomfort from some substances at or below the threshold limit a smaller percentage may be affected more seriously by aggravation of a preexisting condition or by development of an occupational illness. Threshold limits are based on the best available information from industrial experience, from experimental human and animal studies, and when possible, from a combination of the three. The basis on which the values are established may differ from substance to substance protection against impairment of health may be a guiding factor for some, whereas reasonable freedom from irritation, narcosis, nuisance, or other forms of stress may form the basis for others. Three categories of TLVs follow ... 

To better evaluate pollution prevention options, the project attempted to assess the risks posed to individuals and populations exposed to chemical contaminants released from the refinery. An initial risk assessment analysis was performed to identify chemicals requiring further study, and to establish a baseline by which to judge potential risk reduction opportunities. Since change in exposure to benzene was used as a proxy for evaluating relative risk reductions associated with alternative pollution prevention options, the usual uncertainty associated with risk assessments was not a factor in the option analysis. The uncertainty in absolute risk assessments can arise from multiple sources the use of animal study results, difficulties with human studies, variation in individual responses to chemical exposures, the impact of differing dose rates, multiple simultaneous exposure to chem-... 

What are the brain structures or processes where variability accounts for variation in IQ If genetic contributions to inter-individual variation in IQ are in the order of 50% (Devlin et al 1997), which genes are important and what do they control Despite our expanding ability to non-invasively analyse the human brain we cannot count neurons or measure individual myelin sheath thickness. To do this requires studies of clinical populations coming to brain biopsy or autopsy. Work on these populations is slow, expensive, and subject to criticisms of the patient populations or variability due to uncontrollable post-mortem delay effects (Witelson McCulloch 1991). Animals do not have these difficulties. Further, unlike correlative inferential human studies, animal studies can attempt to be causal by actually manipulating the variables of interest. 

As in rodents and other animals, there is much individual variation in human caries experience. In the Vipeholm study, 25% of subjects taking the sticky candies did not develop any cavities over 6 years, whereas a few cavities appeared in control subjects who received a diet that contained little carbohydrate and no refined carbohydrate. A few cavities also appeared in children of the Hopewood House study who received a similar diet. Within 74 junior and senior dental students attending the College of Dentistry at the University of Oklahoma in 1985 (mean age 26 years), the mean DMFT was 8.4 with a variability of 40% about the mean (Fig. 15.10). Two had only one tooth affected and two others had, respectively 15 and 16 teeth affected. The variation is due to differences in microbiota, dietary carbohydrate intake, sahva flow, fluoride exposure, and acquired immunity (Table 15.1). 

A further consideration that is very important in whole animal studies is the inter-individual variation in response to treatment. This variation can be quite high between animals and it has been recommended that at least 10 animals per treatment be used if one wishes to quantify apoptosis in a tissue (4). A final item that can become a concern is those situations where the basal apoptotic index is very low (<0.1 %), in which case counting sufficient apoptotic bodies to obtain an index of sufficient confidence may warrant the counting of far more cells than originally intended, perhaps as many as 6000 (3,44). 

A series of reviews describing nicotine metabolism has recently appeared [2], Specific topics covered include the biosynthesis and metabolism of nicotine and related alkaloids [3], an overview of mammalian nicotine metabolism [4], the role of cytochrome P450 in nicotine metabolism [5], nicotine metabolism beyond cotinine [6], N-oxidation, A -methylation, and N-conjugation reactions of nicotine [7], extrahepatic metabolism of nicotine and related compounds [8], metabolism of the minor tobacco alkaloids [9], analysis and levels of nicotine and metabolites in body fluids [10], kinetics of nicotine and its metabolites in animals [11], pharmacokinetics of (S)-nicotine and metabolites in humans [12], and sources of inter-individual variation in nicotine pharmacokinetics [13]. Another recent review described variables which affect nicotine metabolism [14]. Several compilations of studies or reviews on the tobacco-specific A-nitrosamines are available [15-18]... 

Reproductive Toxicity. The only available human study shows no adverse effects on the sperm of men exposed for a chronic period (Tuohimaa and Wichmann 1981). Further intermediate screening tests assessing In vitro sperm fertilization ability would be useful in determining that this substance poses no reproductive risk. More information on the effects of inhalation exposure on FSH levels is needed in order to confirm that the decreases in FSH noted in men exposed for an acute period are exposure related and not a result of individual variations or not just extremely transient (Pedersen and Cohr 1984b). Multigenerational animal studies could be considered. 

It should be noted that all three of these variants carry histidine residues within or near the chromophore, suggesting the active involvement of histidine in photochemical reactions. Histidine, however, appears to play different roles depending on whether it is situated outside the chromophore at position 203 (PA-GFP and KFPl) or within the chromophore (Kaede). Studies by Ando et al. [22] and Chudakov et al. [24] have addressed the molecular mechanisms behind color variation occurring within individual coral animals. When exposed to sunUght, the tentacles and disk of the coral animals turn a shade of red in proportion to the degree of photoconversion. Then they revert to their previous colors as newly-synthesized proteins are added. Mechanisms such as this may be responsible for the great variety of color observed in coral reefs. 

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