NOAELs

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

No-Obscncd-Advcrsc-Effcct-Levcl (NOAEL) In dose-response experiments, an exposure level at which there arc no statistically or biologically significant increases in the frequency or severity of adr erse effects between the exposed population and its appropriate control some effects may be produced at this IcN cl, but they arc not considered to be adverse, nor precursors to specific... 

After the critical study and toxic effect have been selected, the USEPA identifies the experimental exposure level representing the highest level tested at which no adverse effects (including the critical toxic effect) were demonstrated. This highest "no-obserx cd-adversc-effcct-lever (NOAEL) is the key datum obtained from the study of the dose-response relationship. A NOAEL obserx ed in an animal study in which the exposure was intermittent (such as five days per week) is adjusted to reflect continuous exposure. 

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. 

A UF of 10 is used when a NOAEL derived from a subchronic instead of a chronic study is used as the basis for a chronic RfD. 

A UF of 10 is used when a LOAEL is used instead of a NOAEL. This factor is intended to account for the uncertainty associated with e.xtrapolating from LOAELs to NOAELs. 

To calculate the RID, the appropriate NOAEL (or the LOAEL if a suitable NOAEL is not available) is divided by the product of all of the applicable uncertainly factors and the modifying factor. 

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. ... 

Development of subchronic RfDs parallels the development of chronic reference doses in concept the distinction is one of e.xposurc duration. Appropriate studies are evaluated and a subchronic NOAEL is identified. The RfD is derived from the NOAEL by the application of the UFs and MF, as outlined above. When experimental data arc available only for shorter e.xposurc durations than desired, an additional uncertainly factor is applied. This is similar to the application of the uncertainly factor for duration differences when a chronic RfD is estimated from subchronic animal data. On the other hand, if subchronic data are missing and a chronic oral RfD derived from chronic data exists, the chronic oral RfD is adopted as the subchronic oral RfD. Ill this instance, there is no application of an uncertainly factor to account for differences in exposure duration. 

Both NOEL and LOEL are based on a wide range of toxic substance effects, while NOAEL and LOAEL are based on only adverse effects. Neither set of parameters take into account the individual variation in susceptibility. 

Comment When using data for LOELs, LOAELs, NOELs, or NOAELs, it is important to be aware of their limitations. As discussed in the chapter, statistical uncertainty exists in the determination of these parameters due to the limited number of animals used in the studies to determine the values. However, any toxic effect might be used for the NOAEL and LOAEL so long as it is the most sensitive toxic effect and considered like it to occur in humans. 

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). 

Neurotoxicity is the major end-point for the methyl-tins, with a NOAEL of approximately 0.6 mg/kg body weight based on neuropathology for dimethyltin limited data for monomethyltin preclude the derivation of a NOAEL. No neurotoxicity was found with dibutyltin or mono- and dioctyltins no information is available for monobutyltin. 

NOAELs for mono- and dioctyltin have been determined to be 0.87 and 0.23 mg/kg body weight per day, respectively, although the value for monooctyltin is an estimate, because the study was performed using a mixture. Other information suggests that dioctyltin is the more immrmotoxic of the two compormds. 

Developmental toxicity is shown by the disubstituted methyl-, butyl-, and octyltins, but not by the corresponding monosubstituted compounds. The major reported effect is teratogenicity, with effects on fetuses shown at doses close to maternally toxic ones in most cases. NOAELs for dimethyltin, dibutyltin, and dioctyltin are 10 (10), 2.5 (1.0), and 45 (30) mg/kg body weight per day for teratogenicity (maternal toxicity NOAELs in parentheses). 

Immunotoxicity, consistently effects on thymus weight but also measures of functional immunotoxicity, is demonstrated for dibutyltin and mono- and dioctylins. A NOAEL could not be determined for dibutyltin, but the lowest dose reported as causing effects was 2.5 mg/kg body weight per day (as dibutyltin dichloride). 

Tin compound Species Test material Exposure period and dose Effects NOAEL/LOAEL (mg/kg body weight per day) Reference... 

Monomethyltin Rat MMTC 8 weeks at 0, 30, 150, and 750 mg/kg diet = 0, 1.5, 7.5, and 37.5 mg/kg body weight Fertility, developmental toxicity, and maternal toxicity (screening) NOAEL = 7.5 Appel Waalkens-Berendsen (2004a)... 

Dimethyltin Rat DMTC Gestation days 7-17 at 0,5, 10, 15, and 20 mg/kg body weight Maternal toxicity reduction in fetal body weight reduced thymus weight in dams LOAEL=15 NOAEL=10 Noda (2001)... 

Monobutyltin Rat MBTC Gestation days 7-17at0, 50, 100, 200, and 400 mg/kg body weight Maternal toxicity thymic atrophy dose-dependent developmental toxicity fetuses with visceral or skeletal abnormalities NOAEL >400 Noda etal. (1992)... 

Dibutyltin Rat DBTC Gestation days 7-15at0, 2.5, 5, 7.5, and 10 mg/kg body weight Maternal toxicity body weight gain Teratogenicity LOAEL = 7.5 NOAEL = 5 LOAEL = 5 NOAEL = 2.5 Ema et al. (1991)... 

Incidence of fetuses with malformations slightly increased LOAEL = 10 NOAEL = 5 ... 

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