Toxicity studies NOAEL

The no observed adverse effect level (NOAEL) is obtained from the most relevant toxicity study. The lowest NOAEL observed on the toxicology studies was 1.5 mg/kg/day based on reduced weight gain in a 2-year chronic feeding study in rats. An estimate of no more than 30 days of use or handling per year was used in the calculation of the U.S. EPA safety factors. 

Because bromomethane tends to volatilize and exists mainly as a gas at room temperature, only two oral toxicity studies have been performed (Boorman et al. 1986 Danse et al. 1984). Both studies were performed by administering bromomethane dissolved in oil to rats and both studies reported that irritation of the stomach was the chief effect. The 13-week study by Danse et al. (1984) identified a NOAEL of 0.4 mg/kg/day and a LOAEL of 2 mg/kg/day. An intermediate-duration oral MRL of 0.003 mg/kg/day was derived from the NOAEL (0.4 mg/kg/day) by adjusting for intermittent exposure (5 days/week) and dividing by an uncertainty factor of 100 (10 for extrapolation from animals to humans, and 10 for human variability). 

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

If local effects are clearly identified after repeated dosing, a NOAEL and/or LOAEL should be derived for these effects in addition to NOAEL and/or LOAEL derived for systemic effects. Supportive evidence for the occurrence or absence of local effects after repeated dermal and inhalation exposure may be available from the total toxicity profile of the substance. It should be noted that lack of evidence for local effects in any type of study (i.e., skin or eye irritation, sensitization, repeated dose toxicity study by routes other than the route of interest) does not exclude the possible occurrence of local effects upon repeated respiratory or dermal exposure (EC 2003). 

The maximum hormetic stimulatory response is typically a 30%-60% increase of the control value, and this appears to be the case across systems, whether the system is a plant, fish, cell line, mammal, or bacteria. The hormetic response is typically observed at dose levels at 1/10-1/5 of the NOAEL and up to just below the NOAEL. The frequency with which hormesis occurs in toxicity smdies may be quite high. An analysis of several hundred articles selected from a large database of published toxicity studies showed a frequency of 40% (Calabrese 2005). 

Dourson and Stara (1983) evaluated ratios of subchronic to chronic exposure for either NOAELs (30 ratios), LOAELs (22 ratios), or their combination (52 ratios) derived from the toxicity studies compiled by Weil and McCoUister (1963), see above. For more than half of the observed chemicals, ratios were 2 or less, and approximately 96% of the ratios were below a value of 10. According to the authors, this supports a 10-fold UF to account for estimating an ADI from a subchronic effect level for a chemical if a chronic level is unavailable. 

Dourson et al. (1996) noted that if data are only available from one chronic study on which to base the estimation of a sub-threshold dose, the question could be asked whether data from chronic studies in other species or data from different types of bioassays (e.g., reproductive or developmental toxicity) would yield lower NOAELs. The uncertainty related to this issue must therefore be addressed and, according to the authors, the default approach to address this uncertainty is to apply a 3- or 10-fold UF, based on the assumption that the critical effect can be discovered in a reasonably small selection of toxicity studies. With a reference to some analyses performed within this area, the authors suggested the use of a UF to account for missing bioassays however, the quantification of this UF was considered to require additional work. 

In the main study, a number of effects were observed at the LOAEL and, based on the toxicity data of the individual compounds, most of these effects were expected. A few effects seen in the toxicity studies with the individual compounds had disappeared in the combination, whereas some effects not seen in the range-hnding studies with the individual compounds appeared in the combination. Only minor treatment related effects were observed in the NOAEL. 

Maximum concentration (Cmax) and exposure (AUQ in toxicity studies at NOAEL using the most sensitive species, based on the concentrations of drug unbound to plasma proteins (for which substantial corrections may be necessary if plasma protein binding in one or more species is above 95%)... 

Intermediate oral MRLs for all three cresol isomers could have been calculated based on NOAEL values of 30 mg/kg/day for neurological effects in two-generation reproductive studies in rats (BRRC 1989a, 1989b, 1989c). However, these intermediate oral MRLs were not derived because they would have been less protective than the acute MRLs. This apparent anomaly reflects the fact that lower doses were employed in the developmental toxicity study used as the basis for the acute MRLs than in longer term studies. Dermal MRLs were not derived for cresols due to the lack of an appropriate methodology. 

The DNEL derivation starts with the determination of the appropriate dose descriptor. The most common dose descriptor for teratogenic effects is the NOAEL. But when a NOAEL cannot be identified, the lowest observed adverse effect level (LOAEL) or a calculated benchmark-dose value (BMD ) may serve as a basis for the DNEL derivation. If several toxicity studies are available addressing teratogenicity, usually the lowest dose descriptor is chosen. 

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). 

Approaches to duration adjustment are reviewed in Kimmel et al. (2006). Prior to derivation of NOAELs, LOAELs, or BMDs/ BMCs, the toxicity data are adjusted to a continuous exposure scenario. For oral studies, a daily exposure adjustment is made (e.g. a five days per week exposure is converted to seven days per week). For inhalation exposures, a concentration x time (c x t) adjustment is made. Traditionally, the inhalation exposure adjustment has not been done, because of concerns about peak versus integrated exposure and the likelihood of a threshold for effects. However, a review of the RfD and RfC processes by the USEPA recommended that inhalation developmental toxicity studies be adjusted in the same way as for other end-points (USEPA, 2002b). Derivation of a human equivalent concentration for inhalation exposures is intended to account for pharmacokinetic differences between humans and animals. 

A chronic oral RfD of 1.5 mg chromium(III)/kg/day has been derived and verified by EPA for insoluble salts of chromium(III) (e.g., chromium oxide and chromium sulfate) (IRIS 2000a). The RfD is based on a NOAEL for systemic effects in rats fed 1,800 mg chromium(III)/kg/day for 5 days/week for 600 feedings (840 total days) in the study by Ivankovic and Preussmann (1975). EPA has determined that the data are inadequate for the development of an RfC for chromium(III) due to the lack of relevant toxicity study addressing the respiratory effects of chromium(III) (IRIS 2000a). 

Effects in Adult Animals in Chronic Toxicity Studies Doses Tested in EFD Study (NOAEL or highest dose tested) Effects on Fertility, Pregnancy and Development Clinical Dose Pregnancy Category... 

In the toxicity studies the maximum administered dose was identified as the NOAEL. A traditional lethal dose study was not performed. Instead, the relationship between dose levels and toxicity were evaluated. These studies demonstrated that r-haGAL had extremely low toxicity. It was unlikely that a clear toxic dose could have been identified for r-haG AL given that r-haGAL cannot be sufficiently concentrated to deliver a lethal dose and test animals... 

Once an assessment has determined that the data indicate human risk potential for reproductive and developmental toxicity, the next step is to perform a quantitative evaluation. Dose-response data from human and experimental animal reproductive and developmental toxicity studies are reviewed to identify a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL), and/or to derive a benchmark dose (BMD). Duration adjustments of the NOAEL, LOAEL, or BMD are often made, particularly for inhalation exposures when extrapolating to different exposure scenarios. Such adjustments have not been routinely applied to developmental toxicity data. The subcommittee recommends that duration adjustments be considered for both reproductive and developmental toxicity... 

UFs for reproductive and developmental toxicity applied to the NOAEL often include 10-fold factors for interspecies and intraspecies variation. Additional factors might be applied to account for other uncertainties or for additional information that might exist in a database. For example, in circumstances in which only a LOAEL is available, it might be necessary to use an additional UF uncertainty factor of up to 10, depending on the sensitivity of the endpoints evaluated, the adequacy of the tested dose, or general confidence in the LOAEL. An additional uncertainty factor of 3-10 has been used by EPA (1996a) to account for database deficiencies, particularly the lack of reproductive and developmental toxicity studies. 

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