Exposure extrapolation duration chronic study

The authors noted that it may be expected that the NOAELs from subacute/subchronic smdies tend to be larger than NOAELs from chronic studies and it was considered that the GM ratios for the NOAELs assessed in the studies most likely overestimated the median of the distribution of the extrapolation factor for duration of exposure. The authors also noted that it is very likely that the databases used in these studies overlap each other significantly. It was also pointed out that the distributions presented in Table 5.8 were based on rather variable exposure periods for the subchronic NOAELs, included interspecies variation (no matching for species) for... 

There are a number of studies that provide good quantitative dose- response data by the inhalation route, and inhalation MRLs have been derived for acute, intermediate and chronic inhalation exposure. The acute value is based on a study in rats in which exposure to 31 ppm for 8 hours caused altered levels of brain neurotransmitters, while 16 ppm had no effect (Honma 1987). The MRL of 0.05 ppm was obtained by adjusting the NOAEL (16 ppm) for less than continuous exposure (8 hour/day) and dividing by an uncertainty factor of 100 (10 for extrapolation from animals to humans, and 10 for human variability). The intermediate-duration inhalation MRL is based on a 3-week study in rats in which exposure to 10 ppm resulted in decreased brain neurotransmitters, while 5 ppm did not (Honma et al. 1982). The intermediate MRL of 0.05 ppm was derived from the NOAEL (5 ppm) by dividing by an uncertainty factor of 100, as described above. The chronic... 

Vermeire et al. (1999) reviewed several studies comparing NOAELs from chronic and subacute/subchronic studies in order to evaluate the distribution of the extrapolation factor for duration of exposure. The ratios of observed NOAELs from oral studies using historical data for various compounds were calculated. The most likely distribution of the ratios was considered to be lognormal and the parameters of the distributions of the ratios were estimated, see Table 5.8. 

A chronic-duration inhalation MRL was not derived for chlorine dioxide because chronic inhalation exposure studies in humans or animals are not available. An approach using an uncertainty factor for extrapolating from intermediate- to chronic-duration exposure was not used because it is not known whether respiratory irritation, observed during intermediate-duration inhalation exposure to chlorine dioxide, might result in more persistent effects in cases of chronic-duration exposure. Furthermore, it is not likely that humans would be chronically exposed to significant concentrations of chlorine dioxide vapors in environmental or occupational settings. 

The inhalation RfC for naphthalene was 0.003 mg/m3, and this RfC was derived from a chronic (2-year) NTP inhalation study in mice using exposures of 0, 10, or 30 ppm (NTP, 1992). Groups of mice were exposed for 5 days a week and 6 hours a day. This study identified a LOAEL of 10 ppm. A dose-related incidence of chronic inflammation of the epithelium of the nasal passages and lungs was observed. This LOAEL concentration was normalized by adjusting for the 6-hour-per-day and 5-day-per-week exposure pattern. A LOAEL of 9.3 mg/m3 was obtained was derived by converting 10 ppm first to mg/m3 and then duration-adjusted levels for 6 h/day and 5 days/week for 103 weeks. An UP of 3000 was used, where 10 was for the interspecies (mice to humans) extrapolations, 10 for intraspecies variation in humans, 10 for using a LOAEL instead of a NOAEL, and 3 for database deficiencies. 

The oral RfD for naphthalene was 0.02 mg/kg/day, and a study by Battelle (1980) was used to calculate the RfD. Decreased body weight was the most sensitive end point in groups of Lischer 344 rats given 0, 25, 50, 100, 200, or 400 mg/kg for 5 days/week for 13 weeks. These doses were also duration-adjusted to 0, 17.9, 35.7, 71.4, 142.9, and 285.7 mg/kg/day, respectively. The NOAEL for a > 10% decrease in body weight in this study was 71 mg/kg/day. The UL of 3000 was based on 10 for rats to humans extrapolation, 10 for human variation, 10 to extrapolate from subchronic to chronic, and 3 for database deficiencies including lack of chronic oral exposure studies. 

An MRL of 0.06 mg/kg/day was derived for chronic-duration ( 365 days) oral exposure to DEHP based on a NOAEL of 5.8 mg/kg/day for testicular pathology in male rats that were exposed to DEHP in the diet for up to 104 weeks in a chronic toxicity study (David et al. 2000a). The LOAEL in this study was 29 mg/kg/day for bilateral aspermatogenesis. The chronic MRL was derived by dividing the 5.8 mg/kg/day NOAEL by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). 

In the risk assessment, some steps are not well described. For example, subchronic toxicity studies and not chronic toxicity studies are used in the risk assessment. Exposure duration and frequency considerations are not discussed. Route-to-route extrapolation is considered acceptable implicitly, without further evaluation of the various issues involved. The rationale for using a dermal absorption default of 10 %, in the absence of data is also not discussed. 

This model has a straightforward structure and is simple to use. It is based on studies carried out in part for the specific purpose of model development. However, not all of the required information is publicly available. The databases are not described at the study level the exposure data are only available in classes, although more detailed information is available on request. The choice of the statistics is not discussed. In the risk-assessment approach, some steps are not clearly presented. Sub-chronic toxicity studies, and not chronic toxicity studies, are used in the risk assessment. Exposure duration and frequency considerations are not discussed. Route-to-route extrapolation is considered acceptable implicitly, without further evaluation of the various issues involved. The rationale for using a dermal absorption default of 10 %, in the absence of data, is not discussed. 

Goldman et al. 1988). The subcommittee believes, however, that because the exposure duration of the critical study (7 days) is too short to be considered a subchronic exposure study, a factor of 10 should be assigned to UFs to account for the greater uncertainty involved with extrapolating such data to chronic exposures. 

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