Study population derivation

Arentz-Hansen et al. (2004) ( continuation of Lundin et al, 2003) 9 CD subjects who had history of oats exposure ( 5/9 from same study population) Derivation of polyclonal T cell lines In vitro duodenal mucosal cultures were challenged with either pepsin or Avenin-reactive T cell lines recognized avenin peptides in the context of HLA-DQ2 A substantial proportion of the avenin-reactive T cell appears to be specific to avenin Some CD patients have avenin-reactive mucosal T cells that can cause mucosal inflammation... 

The dose-response relationship for each biopharmaceutical can be analyzed, and the variation between subjects in the study population can be derived. A representative curve, presented as drug concentration versus effect intensity, is shown in Figure 5.8. It indicates that variation exists in intensity at a given drug concentration and in drug concentration at a given level of intensity. The steepness or slope of the... 

A model of the randomly colling form of polylrll) based on minimum-energy conformers of UpU is described. The blend of conformers is chosen to fit the C—C rotational populations derived in NMR studies of UpU and poly(rU) and to match the experimental unperturbed dimensions of the poly(rU) chain. In addition, estimates of loop closure based on the model are comparable to the sizes of loops most frequently seen In the model oligonucleotides. Approximately 60% of the conformers constituting the model are characterized by stacked, extended C2 -endo ra cmy = tg g+ rotations. 

Cohort studies of rare adverse events would be useful, but are generally not feasible, particularly for economic reasons. One promising alternative approach is the use of large linked databases. The databases appropriate for such studies are derived from defined populations, such... 

Genetic studies (primarily derived from population, family, twin, and adoptive studies) suggest that certain depressive disorders may have a genetic loading, especially bipolar and imipolar depression. 

Accordingly, ATSDR used maternal hair mercury levels as the exposure measurement to derive a chronic MRL for methylmercury. While hair analysis can be confounded by outside sources of contamination (e g., as might occur in certain occupational settings) (Hac and Krechniak 1993), the study population used as the basis of the chronic oral MRL for methylmercury is far removed from external or industrial sources of mercury, effectively eliminating this as a consideration for the following analysis. 

Two notes deserve mention. First, Dr. Rogan provided evidence that his NOAEL might be overstated by a factor of two, due to the use of an analytical method that is known to overstate PCB concentrations. As a result, a NOAEL of 0.05 pg/kg/day can be reported for the studies reviewed by Tilson et al. (1990) for the most sensitive population (i.e., embryos and children). (Note, some panehsts thought an additional factor of 10 should be apphed to his NOAEL to account for sensitive populations, but other panelists disagreed.) Second, the extrapolated NOAEL for the Tryphonas study was derived as follows The LOAEL in rhesus monkeys of 5 pg/kg/day was divided by a factor of 10 to convert the LOAEL to a NOAEL of 0.5 pg/kg/day in monkeys. This NOAEL was then divided by 3 to account for interspecies variation. Therefore, ATSDR calculated the NOAEL in the non sensitive human population as 0.166 pg/kg/day, rounded up to 0.2 pg/kg/day. To account for the most sensitive population, such as the developing embryo and fetuses, ATSDR divided the 0.2 pg/kg/day by a factor of 10 and resulted in an MRL of 0.02 pg/kg/day. As a result, ATSDR s MRL (i.e., 0.02 pg/kg/day) is lower than the NOAEL in the most sensitive human subpopulation reported in the studies reviewed by Tilson et al. (1990) (i.e., 0.05 pg/kg/day). 

The standard approach for developing an RfD involves selecting a critical study that is well conducted and identifies the most sensitive end point of toxicity. The current EPA RfD is based on data from a poisoning episode in Iraq. However, MeHg exposures in that study population were not comparable to low-level, chronic exposures seen in the North American population, and there are a number of uncertainties associated with the Iraqi data. In light of those considerations and more recent epidemiological studies, the committee concludes that the Iraqi study should no longer be considered the critical study for the derivation of the RfD. 

Before new drugs can be approved for marketing, their efficacy and safety must be tested in animal and human population studies. Data derived from these studies are presented using the following terminology ... 

The limitation of the data is that the study population from which the variance measure was derived was rather homogeneous, and the estimates were minimum requirements (Andersen et al., 2007a). 

Numerous studies of the general US population derived from several NHANES evaluations have described associations between BLLs and renal function. They and the Normative Aging Study (Kim et al. 1996 Tsaih et al. 2004) and the Swedish Women s Health Study (SWHS) (Akesson et al. 2005) led NTP to conclude that there is sufficient evidence available for an association between current [BLLs] <5 pg/dL in adults, measured at the time of study, and reduced kidney Action in general populations (NTP 2012, p. 102). For example, in an NHANES study of BLL and renal function in nearly 10,000 adults recruited in 1999-2002, Muntner et al. (2005) described an increased risk of CKD, defined as an estimated GFR under 60 mL/min/1.73 m. Compared with those in the lowest quartile of BLL (under 1.06 pg/dL), people in the highest quartile (over 2.47 p dL) were 2.72 (95% Cl 1.47, 5.04) times more likely to have CKD. In support, Navas-Aden et al. (2009), in a comparable study of nearly 15,000 adults evaluated during 1999-2006, observed reduced GFR in those who had BLLs over 2.4 pg/dL vs those who had BLLs of 1.1 pg/dL or lower (adjusted OR = 1.56 95% Cl 1.17, 2.08). The latter study also observed a... 

---