LOAEL doses

There are several limitations to tliis approach that must be acknowledged. As mentioned earlier, tlie level of concern does not increase linearly as the reference dose is approached or exceeded because the RfDs do not luive equal accuracy or precision and are not based on the same severity of effects. Moreover, luizm-d quotients are combined for substances with RfDs based on critical effects of vaiy ing toxicological significance. Also, it will often be the case that RfDs of varying levels of confidence Uiat include different uncertainty adjustments and modifying factors will be combined (c.g., extrapolation from animals to hmnans, from LOAELs to NOAELs, or from one exposure duration to anoUier). 

Other than the study by Weeks et al. (1979) there are no inhalation studies useful for estimating an intermediate inhalation MRL. Studies in guinea pigs and dogs confirm that 260 ppm hexachloroethane is a serious effect concentration 4/10 guinea pigs, and 1/4 dogs died at this concentration. These studies do not clearly identify a less serious LOAEL that does not have some serious effects. The 48-ppm concentration is aNOAEL for the most sensitive toxicity endpoint in all three species. 

If there are several valid studies addressing the same effect from which different NOAELs could be derived, the highest reliable NOAEL not exceeding any of the reliable LOAELs should be used in the hazard assessment. If the smdies are not quite comparable, i.e., do not examine the same endpoints by equally sensitive methods, expert judgment is used to derive the most relevant NOAEL. When it is not possible to derive a NOAEL, the LOAEL should be used in the hazard assessment. 

LOAEL, although a substantially smaller safety and uncertainty factor may be used when RfD is derived from a NOAEL obtained in a high-quality study in humans. The schematic relationship of NOAEL, LOAEL, and RfD is illustrated in Figure 3.5. Although RfDs are widely used in health protection of the public, it is important to understand that they do not represent thresholds for deterministic responses in humans. 

UFa = Animal to human an Uncertainty Factor up to 10 to be used when extrapolating from animal data to humans and based on the assumption that humans are likely to be more sensitive than animals UFs = Subchronic to chronic an Uncertainty Factor up to 10 to be used when extrapolating from a subchronic study to derive a chronic RfDe UFl = LOAEL to NOAEL an Uncertainty Factor up to 10 to be used when a suitable NOAEL is not available and when a LOAEL is used instead UFd = Incomplete to Complete data base an Uncertainty Factor up to 10 to be used when the available data do not adequately address all possible adverse outcomes in humans... 

A RfD is derived by first examining the available human or animal toxicity data to identify a dose or exposure that corresponds to a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL). The NOAEL is the exposure level at which there are no statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Effects may be produced at this level, but they are not considered to be adverse if they do not result in functional impairment or pathological lesions that affect the performance of the whole organism or which reduce an organism s ability to cope with additional chal-... 

A third uncertainty fector of 10 is added if the animal toxicity data do not define the NOAEL conclusively. Eor example, animal toxicity data may define a LOAEL (lowest observed adverse effect level) but not a NOAEL. In such a case, the reference dose might be estimated from the LOAEL by including an additional uncertainty factor of 10 ... 

Compare and contrast the methods and values used for toluene with those used for the noncancer effects of arsenic. We have sufficient information from arsenic contamination of drinking water in Taiwan and Chile to develop a protective dose for humans ingesting arsenic in drinking water therefore we do not need to extrapolate results from another animal species. Both a LOAEL and NOAEL are available from the drinking water studies from Taiwan. A NOAEL of 0.0008 mg/kg-day and a LOAEL of 0.014 mg/kg-day were reported. Based on these doses, it is clear that arsenic is more toxic to humans than toluene because the arsenic doses needed to cause toxic effects are much lower than those causing toxic effects by toluene. 

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