LOAEL

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-... 

Lowcst-Obsciwcd-Advcrsc-El fcct-Lcvel (LOAEL) In dose-response experiments, the lowest exposure level at which there are statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control group. 

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 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. 

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). 

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

Rat DBTC Gestation days 4-7 at 3.8 mg/kg body weight and above impiantation faiiure LOAEL = 3.8 Harazono and Ema (2003)... 

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)... 

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 ... 

Monooctyltin/ dioctyltin Mouse DOT stabilizer mix (DOT(IOMA) MOT(IOMA) 80 20) Gestation days 6-17 at 0,20, 30, 45, 67, and 100 mg/kg body weight Embryo/fetal malformations Maternal thymus weight LOAEL = 67 NOAEL = 45 LOAEL = 45 NOAEL = 30 Faqi et al. (2001)... 

Short- to medium-term exposure has shown neurotoxicity, developmental toxicity, immunotoxicity, and endocrine disruption to be relevant end-points. Table 24 summarizes the critical studies for each compound and identifies NOAELs or LOAELs. The degree of each of the toxic end-points differs across the group as a whole. For example, tributyltin is well established as an aromatase inhibitor, and dibutyltin appears to have some potency also (exact characterization of the endocrine disrupting capacity of dibutyltin alone is difficult because of the presence of tributyltin as an impurity). Monobutyltin and mono- and dioctyltins have no aromatase inhibiting capacity in in vitro tests. No data are available for this end-point for the methyltins. 

LOAEL lowest-observed-adverse-effect level... 

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). 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and figures may differ depending on the user s perspective. Public health officials and others concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans (minimal risk levels or MRLs) may be of interest to health professionals and citizens alike. 

LOAEL, Less Serious-Animals OnoAEL-Animals... 

Cancer Effect Level-Humans A LOAEL. More Serious-Humans A LOAEL, Less Serious-Humans A NOAEL - Humans... 

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