Uncertainty factors

The LD q is calculated from data obtained by using small groups of animals and usually for only a few dose levels. Therefore, there is an uncertainty factor associated with the calculation. This can be defined by determining the 95% confidence limits for the particular levels of mortaUty of interest (Fig. 7). The 95% confidence limits give the dose range for which there is only a 5% chance that the LD q will be outside. 

Note that if the respective samples had been based on 52 observations each rather than 100 and 5, the uncertainty factor would have been . 94 rather than the observed 2.20. The interval width tends to be minimum when ni = n. ... 

Thus, based on the above, it is not surprising that even under the best conditions an uncertainty factor of approximately 2 is likely in estimates of the plume rise. Despite this somewhat pessimistic introduction, estimations of plume rise are worthwhile and an integral part of the dispersion analysis. Table 2 presents some of the well-known plume rise formulas used in different model approaches. The two major controlling variables which appear in many, if not all, of the plume rise formulas surveyed are ... 

FIGURE 5.31 Subdivision of the 100-fold uncertainty factor showing the relationship between the use of uncertainty factors (above the dashed line) and proposed subdivisions based on toxicokinetics and toxicodynamics. Actual data should be used to replace the default values if available, ... 

Safety factor An uncertainty factor that is used in combination with the no-adverse-effect level data to estimate the safe human dose. 

Toxicologists tend to focus their attention primarily on c.xtrapolations from cancer bioassays. However, tlicrc is also a need to evaluate the risks of lower doses to see how they affect the various organs and systems in the body. Many scientific papers focused on tlic use of a safety factor or uncertainty factor approach, since all adverse effects other than cancer and mutation-based dcvclopmcnUil effects are believed to have a tlu cshold i.e., a dose below which no adverse effect should occur. Several researchers have discussed various approaches to setting acceptable daily intakes or exposure limits for developmental and reproductive toxicants. It is Uiought Uiat an acceptable limit of exposure could be determined using cancer models, but today tliey arc considered inappropriate because of tlircsholds. ... 

The NOAEL is selected based in part on the assumption that, if the critical toxic effect is prevented, then all toxic effects are prevented. The NOAEL for the critical toxic effect should not be confused with the "no-obscrx cd-cffcct-lcvel" (NOEL). In some studies, only LOAEL rather than a NOAEL is available. The use of a LOAEL. however, requires the use of an additional uncertainty factor (as seen below). 

The RfD is derived from the NOAEL (or LOAEL) for the critical toxic effect by consistent application of uncertainty factors (UFs) and a modifying factor (ME). The uncertainty factors generally consist of multiples of 10 (although values less than 10 are sometimes used), with each factor representing a specific area of uncertainty inherent in the extrapolation from the available data. The bases for application of different uncertainty factors are explained below. 

In addition to the UFs listed above, a modifying factor (MF) is also applied. An MF ranging from >0 to 10 is included to reflect a qualitative professional assessment of additional uncertainties in the critical study and in the entire data base for the chemical not e.xplicitly addressed by the preceding uncertainty factors. The default value for the MF is 1.0. 

The inhalation RfD is derived from the NOAEL by applying uncertainty factors similar to those listed above for oral RfDs. A UF of 10 is used when e.Ktrapolating from animals to humans in addition to the calculation of the human equivalent dose, to account for interspecific variability in sensitivity to the to. icant. The resulting RfD value for inhalation c. posure is generally reported as a concentration in air in mg/m for continuous, 24 hour/day c. posurc, although it may be reported as a corresponding inhaled intake (in mg/kg-day). A human body weight of 70 kg and an inhalation rate of 20 nv /day are used to convert between an inhaled intake e.xprcsscd in units of mg/kg-day and a concentration in air e. pressed in mg/m. ... 

This large volume indicates that there is cither no health problem or there is considerable uncertainty (i.e., the product of the uncertainty factors is large) in estimating a reference dose for atrazine. 

Uncertainty factors applied are precautionary ones. In addition to an uncertainty factor of 10 for intraspecies... 

Table 28 outlines the critical end-points for the organotin species and the estimated PNECs derived using appropriate uncertainty factors. For the purposes of comparability, all values have been converted to the chloride salt. 

There are insufficient data to conduct a probabilistic estimate of no-effect concentrations. For each of the organotins, the following outlines the reasoning for selection of studies and application of uncertainty factors ... 

Monomethyltirf. Acute toxicity studies were identified for monomethyltin for algae, invertebrates, and fish. Chronic NOECs were available for algae and invertebrates. A chronic NOEC of 0.007 mg/1 for monomethyltin chloride in Scenedesmus subspica-tus was the lowest reported result. Since there were no long-term test results available for fish, it was necessary to apply an uncertainty factor of 50 to the critical study. 

Monobutyltirr. Four acute toxicity studies were identified for monobutyltin chloride. The critical study was an acute EC50, based on immobilization, for Daphnia magna at a concentration of 25 mg/1. All four tests were acute, and, in the absence of long-term tests, it was decided to apply an uncertainty factor of 1000. 

Dibutyltin. A larger data set exists for dibutyltin, including both acute and long-term test results. The lowest concentration identified was a chronic NOEC of 0.015 mg/1 for Daphnia magna exposure to dibutyltin chloride. Long-term values were available across three trophic levels, and, therefore, an uncertainty factor of 10 was considered appropriate. 

Organotin End-point Uncertainty factor Estimated PNEC (ug/i)... 

An intermediate-duration oral MRL of 0.0007 mg/kg/day was derived for methyl parathion based on the observation of electrophysiological effects in the central and peripheral nervous systems of male rats exposed to methyl parathion through gavage administration of 0.22 mg/kg/day to the dams on days 5-15 of gestation and days 2-28 of lactation, followed by direct administration of the same dose to the male pups for 8 weeks. More marked effects occurred at the two higher doses, 0.44 and 0.88 mg/kg/day. The effects were dose-related, and were statistically significant at all three dose levels. The MRL was derived by dividing the LOAEL from this study (0.22 mg/kg/day) by an uncertainty factor of 300 (3 for a minimal LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). 

Used to derive an intermediate oral MRL of0.0007 mg/kg/day dose divided by an uncertainty factor of300 (10 for extrapolation from animals to humans, 10 for human variability, and 3 for a minimal LOAEL). 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a minimal risk level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty factors. The default value for a MF is 1. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-efifect level (NOAEL-from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor approach. They are below levels that might cause adverse health effects in the people most sensitive to such chemical-induced effects. MRLs are derived for acute (1-14 days), intermediate (15-364 days), and chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not mean that adverse health effects will occur. 

PBPK models results in more meaningful extrapolations than those generated with the more conventional use of uncertainty factors. 

The chronic-duration oral MRL was derived based on the observation of increased serum levels of alkaline phosphatase (an indicator of hepatotoxicity) in dogs consuming 0.6 mg/kg/day for 1 year (Hoechst 1989c). The choice of this end point is supported by the observation of hydropic hepatic cells in rats that consumed 5 mg/kg/day for 2 years (EMC 1959b). The chronic-duration MRL of 0.002 mg/kg/day was derived by dividing the NOAEL for elevated serum alkaline phosphatase (0.18 mg/kg/day) by an uncertainty factor of 100 (10 for extrapolating from animals to humans, and 10 for human variability). 

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