Toxicity study evaluation NOAEL

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. 

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. 

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. 

The major gap in the available information on GB is the lack of an oral subchronic or chronic toxicity study that demonstrates a clear LOAEL or NOAEL. The absence of that type of data could be addressed by conducting a subchronic oral toxicity study that assesses anti-ChE activity in RBCs and plasma in one or preferably two species. At least one dose between 0 and 0.075 mg/kg per day should be used. If further research reveals that significant toxic effects can be induced by any of the nerve agents evaluated (i.e., GA, GB, GD, or VX) at doses below those that cause significant ChE inhibition, new studies should be conducted reassess the safety of the recommended RfD for GB. 

In general, criteria developed to protect against noncancer effects are based on the assumption that there is a threshold below which no adverse health effects will occur. A critical evaluation of available human health and animal toxicity studies is performed to identify the most sensitive adverse effect relevant to humans. Noncancer exposure criteria are often based on an experimentally defined dose at which no adverse effects were observed (i.e., the no-observed-adverse-effect level - NOAEL). If no adequate NOAEL is available, the lowest dose at which adverse effects were observed (lowest-observed-adverse-effect level - LOAEL) is used. Another commonly used approach is to fit study data to dose-response models to identify appropriate values (e.g., dose corresponding to the upper bound of the 10% response level or BMDLio) as the basis for deriving the exposure criteria. 

A two-generation reproductive toxicity study was used to evaluate fertility in adult rats and viability/ toxicity in their offspring. Reproductive parameters were tested over two generations of drinking water exposure to perchlorate. The reproductive NOAEL is... 

As indicated above in the section on "Genotoxic Effects", it is likely that mirex and chlordecone are tumor promoters and not tumor initiators. Initiators irreversibly alter DNA by a mutation, chromosomal aberration, or other alteration. Promoters act by facilitating the proliferation of previously initiated preneoplastic cells. One of the mechanisms for promotion is believed to involve suppression of inhibitory proliferative control through inhibition of gap-junctional-mediated intercellular communication as well as enzyme induction (Trosko et al. 1983). The results of studies to evaluate the promotional activity potential of mirex in mice indicate that mirex is a mouse skin cancer promoter but exerts this toxicity through a hitherto unknown mechanism that is different from that of phorbol esters, such as TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). Unlike initiation, promotion is a reversible process to a point. This implies, at least in theory, that there may be justification for setting NOAELs for promoters. 

The combined results of these two studies indicate that di-ra-octylphthalate probably has a very low potential to induce developmental toxicity, especially in view of the very high doses that were evaluated. The highest NOAEL values and all LOAEL values from each reliable study for developmental effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 

UFm accounts for the quality and relevance of the database, i.e., accounts for the uncertainties in the establishment of a NOAEL for the critical effect. The UFm includes elements such as (1) the quality of the database, e.g., data on specific toxic endpoints are lacking or inadequate, default value of 1-10 (2) route-to-route extrapolation, e.g., no studies using the appropriate exposure route are available, no default value (3) LOAEL-to-NOAEL extrapolation, e.g., a NOAEL cannot be established for the critical effect, default value of 10 (4) subchronic-to-chronic extrapolation, e.g., no chronic studies on which to establish the NOAEL are available, default value of 10 and (5) nature and severity of toxicity, e.g., the critical effect is toxicity to reproduction, carcinogenicity or sensitization, default value of up to 10. A default value for UFm has not been recommended however, a value from 1 to 100 is generally used. The value is evaluated case-by-case based on expert judgment. 

A Dutch study (Wilschut et al. 1998, as reviewed in Vermeire et al. 1999) has evaluated route-to-route extrapolation on the basis of absorption or acute toxicity data. For oral to inhalation route-to-route extrapolation, the predicted inhalation NAEL was often higher than the observed NOAEL (for inhalation) implicating that the substance was considered less toxic after extrapolation when compared with the experimental observations. For oral to dermal route-to-route extrapolation, the predicted dermal NAEL (for inhalation) was often lower than the observed NOAEL (dermal) implicating that the substance was considered more toxic after extrapolation when compared with the experimental observations. 

Sometimes several dose levels are investigated with the described method normally one starts with a dose from which a pharmacological response is expected, but the dose should be lower than NOAEL. Later, during the course of development, studies at the NOAEL may follow. In the case of evaluation of altered routes of elimination at toxic doses, studies with doses higher than NOAEL may considered as an exception. 

The dose-response evaluation defines the range of doses that produce reproductive and developmental toxicity, the routes of exposure, the timing and duration of exposure, the species specificity of effects, and any pharmacokinetic or other considerations that might influence comparison with human exposure. Much of the focus is on identification of the adverse effect observed at the LOAEL and the NOAEL for the study. 

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