Intraspecies differences

Birds seem comparatively resistant to diflubenzuron acute oral LD50 doses exceed 2000 mg/kg body weight (BW) dietary concentrations <4640 mg/kg FW are tolerated for at least 8 days and forest birds seem unharmed by recommended diflubenzuron application procedures to control pestiferous insects, except for a possible loss in fat reserves. Intraspecies differences in ability to metabolize diflubenzuron are probably large different strains of domestic chickens show significant differences in ability to accumulate and retain this compound. 

Intraspecies differences in sensitivity to 2,3,7,8-TCDD — up to 14-fold — are reported among three strains of mice no reasons were given to account for these differences. Oral LD50 (30-day) values varied from 182 pg 2,3,7,8-TCDD per kg body weight in strain C57, the most sensitive... 

Uncertainty factor An uncertainty factor was not applied to the Leeser et al. (1990) 1-ppm concentration because it is the lowest NOAEL. A factor of 3 for intraspecies differences was applied to the supporting studies because no susceptible populations were identified. The uncertainty factor was applied to the 8-h 5 ppm and 8 ppm concentrations, which resulted in concentrations close to the 8-h 1 -ppm concentration in the... 

As the subject of biochemical genetics has developed, it has become clear that inheritance and mutations govern not only the gross metabolic differences between different species but also intraspecies differences of a lesser magnitude. 

If there are species differences in morphology and physiology between the brains of newborn monkeys, gorillas, chimpanzees, and humans and if these interspecies differences are meaningful with respect to intellectual capacities, how about intraspecies differences in morphology and physiology Is it not probable that they are also meaningful ... 

Intraspecies differences (human-to-human) a default value of 3 (workers), a default value of 10 (general population)... 

If the N/LOAEL has been derived from an animal study, animal intraspecies differences have already to some extent been accounted for in that N/LOAEL. Ideally therefore, the assessment... 

US-EPA (1993) stated that in addition to the standard factors (for inter- and intraspecies differences, less than chronic duration studies, and LOAEL-to-NOAEL extrapolation), an extra factor should be included if the total toxicological database is incomplete, i.e., the so-called modifying factor (ME). It was stated that the magnitude of the MF depends upon a professional assessment of scientific uncertainties of the study and database not explicitly accounted for by the standard factors, e.g., the completeness of the overall database and the number of species tested. The default value for the MF is 1. 

Intraspecies differences refer to variability among humans. They arise from genetic polymorphism and differences in age, gender, health, and nutritional status. The assessment factor for intraspecies differences in the general population is usually assumed to be greater than in the occupational subpopulation, which excludes the very young and very old. 

New advances in boron nntrition research shonld include better characterization of the mechanisms through which boron modulates immune function and insulin release (Hunt 1998). Epidemiological studies should be initiated to identify health conditions associated with inadequate dietary boron (Sutherland et al. 1998). Finally, Dourson et al. (1998) recommend more research on uncertainty factors used in establishing tolerable daily intake values for the protection of human health, with emphasis on variations in interspecies and intraspecies differences in resistance to boron. 

Important intraspecies differences are found in the relative proportions of MAO-A or MAO-B in tissues [e.g., human brain has more MAO-B (about 70%) activity rat brain has more MAO-A]. After administration of an MAOI, intracellular levels of endogenous amines (e.g., NE) increase, but levels of amines not usually found in humans (tryptamine and phenylethylamine) also increase, followed by a compensatory decrease in amine synthesis because of feedback mechanisms. Levels of other amines or their metabolites (i.e., false transmitters) increase in storage vesicles and may displace true transmitters, while presynaptic neuronal firing rates decrease. After 3 to 6 weeks, brain serotonin may return to normal levels and NE levels may decrease. There is a compensatory decrease in the number of receptors, including b-adrenergic receptor-related functions (e.g., NE-stimulated adenyl cyclase). 

For chronic exposure, the subcommittee chose the NOAEL of 10,000 ppm for a 6-hr/d, 2-yr exposure based on a significant increase in the incidence of Leydig cell hyperplasia in treated rats (Collins et al. 1995 Hext and Parr-Dobrzanski 1993). Applying an aggregate uncertainty factor of 300 (3 for interspecies extrapolation, 10 for intraspecies differences, and 10 for deficiencies in the database), the UEL for reproductive and developmental toxicity is... 

FACTORS INFLUENCING DERMAL ABSORPTION 319 Factors Related to the Skin 319 Intraspecies Differences 319 Inter-individual Differences 319 Skin Condition 319 Anatomical Site 320 Skin Metabolism 320... 

In Canada and the USA, there is agreement on the nse of a factor of 10 for interspecies differences and another factor of 10 for intraspecies differences. The US Food Quality Protection Act (FQPA) of 1996 and the Canadian Pest Control Products Act (PCPA) of 2002 require that when establishing food tolerances in the case of threshold effects, an additional tenfold safety factor for the pesticide chemical residue and other sources of exposure be applied to infants and children to take into account potential pre- and post-natal toxicity and completeness of the data with respect to exposure and toxicity to infants and children. A different safety factor for the pesticide chemical residue may be used only if, on the basis of reliable data, such a factor will be safe for infants and children. 

With transgenic and transfection approaches, intraspecies differences should be taken in account. For example, infarct size following 30 min of ischemia and 24 h of reperfusion is highly strain-dependent in rats.226 Furthermore, overexpression of a certain protein with transfection might cause loss of its selectivity.227... 

Although the hepatotoxicity of NDMA has been established unequivocally in numerous acute, intermediate and chronic duration oral studies with animals, relatively few of the studies delineate dose-response relationships and appropriate information regarding thresholds for this effect is not available. As noted for lethality, reported hepatotoxic doses for all species occur in the same general range with variations attributable more to intraspecies differences than treatment schedule or method. Human fatalities due to oral and inhalation exposure to NDMA have been reported in which hemorrhagic, necrotic and cirrhotic alterations in the liver were observed, indicating that NDMA produces similar hepatic effects in humans and animals. Therefore it is reasonable to expect that NDMA also will be hepatotoxic in humans at sublethal doses. 

An additional explanation for the observation that lipid only explains approximately 50% of the variation in internal effect concentration may be that the different lipids of an organism do not evenly contribute to storage in target tissues [128], and that lipid normalisation may thus not be appropriate. The assumption, however, that the internal concentration is a distinct value is not valid. Intraspecies differences do exist and cannot be explained by intraspecies differences in lipid content alone, although the variation in LBB within a population is less than an order of magnitude. 

Historically, risk assessment for noncancer endpoints has been based on the identification of a no observed adverse effect level (NOAEL) from a toxicity study with an animal model. The NOAEL is then divided by appropriate uncertainty factors to take potential inter- and intraspecies differences in response into account. However, this approach does not take into account the size of the toxicity study or the shape of the dose-response curve. The benchmark dose (BMD) approach has been suggested as an alternative to a NOAEL (Crump 1984). A BMD is a dose or concentration that produces a predetermined change (e.g., 10% or 1 standard deviation) in response rate of an adverse effect (called the benchmark response or BMR). A BMDL is the statistical lower confidence limit on the dose or concentration at the BMD. The BMD and BMDL are calculated using mathematical dose-response models, which make appropriate use of sample size and the shape of the dose-response curve (EPA 2009b, 2000a). The BMDL is like a NOAEL (i.e., as a point of departure) and is divided by an appropriate composite uncertainty factor to derive a reference value. 

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