End point dose

The electron dose needed for complete disappearance of all crystalline reflections in the SAED pattern is termed the total end-point dose (TEPD),... 

A similar design was used in 249 patients with schizoaffective disorder who received injectable risperidone for 6 months (initial dose 25 mg in 82% of patients, end-point doses ranging from 25 mg in 49% of patients to 75 mg in one) oral risperidone supplementation was needed in 19% (mean modal dose 3 mg/day) (228). Three patients died during the study with heart attack, stroke, and gastrointestinal bleeding other important adverse events were increases in body weight and body mass index (mean increases 1.4 kg and 0.5 kg/m2), sexual dysfunction (4%), and new-onset diabetes mellitus (0.4%). 

On the basis of its evaluation, the committee s consensus is that the value of EPA s current RfD for MeHg, 0.1 pg/kg per day, is a scientifically justifiable level for the protection of public health. However, the committee recommends that the Iraqi study no longer be used as the scientific basis of the RfD. The RfD should still be based on the developmental neurotoxic effects of MeHg, but the Faroe Islands study should be used as the critical study for the derivation of the RfD. Based on coid-blood analyses from the Faroe Islands study, the lowest BMD for a neurobehavioral end point the committee considered to be sufficiently rehable is for the Boston Naming Test. For that end point, dose-response data based on Hg concentrations in cord blood should be modeled using... 

The committee conclndes that, given these considerations, the results from the Boston Naming Test in the Faroe Islands study should be used. For that end point, dose-response data based on Hg concentrations in cord blood should be modeled. For that data set, the K-power model (K > 1) is the model of choice. This analysis estimates a BMD of 85 ppb and a BMDL of 58 ppb. Using a conversion factor of 5 ppb of blood per ppm of hair, that point of departure approximately corresponds to a BMD based on a hair Hg concentration of 17 ppm and a BMDL of 12 ppm. Those values are veiy close to the values estimated directly from the analysis based on hair Hg concentrations. 

Figure 3.38. Plot of end-point dose (a measure of radiation stability) versus melting or degradation temperature (a measure of thermal stability). (Adapted from Martin et al. [47], (2005) Wiley Interscience used with permission.)...

The plaque assay is desirable because it is very sensitive and only detects infectious viral particles. However, there are viral agents which cannot be supported by cell lines. In these cases other methods must be used. The polymerase chain reaction (PGR), which amplifies DNA or RNA from viral agents, can be used to detect the presence and quantity of viral agents. The amount of RNA or DNA target in the initial sample can be determined by competitive PGR where the quantity of amplified product is compared to a control PGR product where the initial amount of target is known. Quantification is also possible by an end-point dilution method similar to that used to determine a tissue culture infections dose. PGR methods can be very sensitive however. 

Arakawa Wada (1993) dosed rats with mono-methyltin trichloride or dimethyltin dichloride for 10 days at 5 mg/kg body weight per day and reported no effects on thymus weight this is the only study examining immunotoxic end-points for the methyltins. 

Similar results for rats were reported by Crowder et al. (1980). Oral administration of 1 mg/kg/day of methyl parathion (99.9% purity) in com oil on days 7-15 of gestation resulted in increased mortality in pups, relative to controls. Significant difference from controls in a maze transfer test was observed in pups from the treated group. However, use of a single-dose level precluded the assessment of dose-response, and several other behavioral end points were not affected. Furthermore, no information was presented regarding body weights or signs of toxicity in the treated dams. 

In the male offspring whose treatment was continued through 11-12 weeks of age, however, dose-related effects were seen on all the above end points, and these effects were significantly different from controls at all three dose levels (Desi et al. 1998) (see also Section S.2.2.4). The study did not determine the critical period (if any) and duration of exposure for these neurological effects. A limitation of this study is that results specifically for methyl parathion were shown only for the somatosensory electrocortico-gram the other results for this chemical were stated in the text, but not shown. 

Some animal studies indicate that dietary exposure to methyl parathion causes decreased humoral and cellular responses (Shtenberg and Dzhunusova 1968 Street and Sharma 1975). A more recent, well-designed animal study that included a battery of immuno/lymphoreticular end points showed few effects at the nonneurotoxic doses tested (Crittenden et al. 1998). No adequate studies are available in humans to assess the immunotoxic potential of methyl parathion. Therefore, studies measuring specific immunologic parameters in occupationally exposed populations are needed to provide useful information. Further studies are also needed to investigate the mechanism for methyl parathion-induced immunotoxicity since this information would help to identify special populations at risk for such effects. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically-based dose-response model which quantitatively describes the relationship between target tissue dose and toxic end points. These models advance the importance of physiologically based models in that they clearly describe the biological effect (response) produced by the system following exposure to an exogenous substance. 

Tables (3-1, 3-2, and 3-3) and figures (3-1 and 3-2) are used to summarize health effects and illustrate graphically levels of exposure associated with those effects. These levels cover health effects observed at increasing dose concentrations and durations, differences in response by species, minimal risk levels (MRLs) to humans for noncancer end points, and EPA s estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs), Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs).

LOAEL A Lowest-Observed-Adverse-Effeet Level (LOAEL) is the lowest dose used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific end point used to quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key number 18 (h q)erplasia) is a Less serious LOAEL of 10 ppm. MRLs are not derived from Serious LOAELs. 

These results demonstrate that immunotoxicity may be a sensitive end point of endosulfan-induced toxicity following exposure to low doses for sufficient durations. The highest NOAEL value and all reliable LOAEL values for immunological effects in each species in each duration category are recorded in Table 2-2 and plotted in Figure 2-2. 

No acute-duration oral MRL was derived for endosulfan because no suitable end point was available among the reliable acute-duration studies. The lowest LOAEL, 1.8 mg/kg/day, was for a serious end point, convulsions in pregnant rabbits, appearing 10 days after the start of daily gavage dosing in the EMC (1981) study. Because animals from both the control and the test groups developed ascites, and six rabbits were added without concurrent controls, the reliability of these results is questionable. 

The intermediate-duration oral MRL was derived based on the observation of decreases in humoral and cell-mediated immune responses in rats consuming 0.9 mg/kg/day for 22 weeks (Banerjee and Hussain 1986). Choice of this end point is supported by the observation of similar effects in rats at higher doses following ingestion for shorter periods (Banerjee and Hussain 1986, 1987) and decreased neutrophils and... 

Immunotoxicity. Limited information is available regarding the effects of endosulfan on the human immune system. However, specially designed studies using rats indicate that both humoral and cellular immune responses are depressed by ingested endosulfan at doses that do not induce any overt signs of toxicity (Banerjee and Hussain 1986,1987). In vitro studies support the possibility that endosulfan affects immune system function (Das et al. 1988). These results demonstrate that immunotoxicity may be a more sensitive end point of endosulfan-induced toxicity than other end points, and humans may be at risk for adverse immune effects following exposure to endosulfan. An intermediate-duration oral MRL was derived based on the observation of depressed immune responses (Banerjee and Hussain 1987). 

Dose and end point used for MRL derivation 0.45 mg/kg/day depressed immune response. 

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