Dose-response relationships LOAELs

No dose-response relationship can be established for the developmental toxicity of methyl parathion from the available database. All reliable LOAEL values in rats for developmental effects for the acute- and intermediate-duration categories are recorded in Table 3-3 and plotted in Figure 3-2. 

Figure 3.2 Dose-response relationship with description of NOAEL and LOAEL.

Before we plunge into the world of carcinogens, we should note that all of the toxic phenomena we have described exhibit dose-response relationships and that LOAELs and NOAELs can be identified for all. As we shall see in later chapters these quantitative features of toxic phenomena are at center stage when we begin to examine risk to exposed populations. 

Dose-response relationships for two animal carcinogens, strikingly different in potency, are presented in Tables 6.2 and 6.3. The type of information presented in the tables is the usual starting point for risk assessments as we shall see, human exposures to these carcinogens are very much less than the NOAELs and LOAELs from the animal data. 

Animal data are available for intermediate exposures by the inhalation and dermal routes of exposure. No animal data were located by the oral route. Most of these studies found no evidence of toxicity in any of the exposure conditions used in each (Carpenter et al. 1976 Bruner 1984 Lock et al. 1984 NTP/NIH 1986). However, the lack of toxicity in these studies has not been verified by more than one study using the same fuel oil, species, and/or route of exposure. In one aerosol inhalation study (Dalbey et al. 1987) there were positive findings for respiratory, hematological, and body weight effects at higher doses than those used in the studies by Carpenter et al. (vapor) (1979) and Lock et al. (aerosol) (1984). However, MRLs cannot be derived from these data because the Dalbey et al. study was not designed to test for a dose-response relationship, and therefore, the exact LOAEL(s) could not be determined for these effects. 

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. 

WHO/IPCS (1994, 1996, 1999) have adopted the approach that in simations where a NOAEL has not been achieved but the data on effects are of sufficient quality to be the basis of the risk assessment, a NAEL should be developed by the application of an appropriate UF to the LOAEL. According to WHO/IPCS (1994), UFs of 3, 5, or 10 have been used previously to extrapolate from a LOAEL to a NOAEL depending on the nature of the effect(s) and the dose-response relationship. A BMD may be developed as an alternative to the UF in extrapolating to the NOAEL. 

In relation to the dose-response curve, KEMI (2003) stated that the slope always has to be considered. A moderate assessment factor (not further specified) may provide an adequate MOS if the dose-response relationship is relatively steep, but may not be sufficiently conservative if the dose-response curve is relatively shallow, see Figure 5.6. In relation to extrapolation from LOAEL to NOAEL, KEMI considered that analysis of several databases does support the statement that a... 

In general, the use of LOAEL/NOAEL ratios to estimate a NOAEL from a LOAEL is questionable as these ratios reflect more the applied intervals between the dose levels in the studies (dose spacing, which is dependent on the study design), rather than the steepness of the dose-response relationship, i.e., the inherent toxicity. It has also been pointed out that there is no guarantee whatsoever that at one dose interval lower (extrapolation from a LOAEL to a NOAEL), the effect would be statistically nonsignificant. 

According to WHO/IPCS (1994), UFs of 3, 5, or 10 have been used previously to extrapolate from a LOAEL to a NOAEL depending on the nature of the effect(s) and the dose-response relationship, see Section 5.7. 

The dose response relationship in this study was inconsistent, but the weight of evidence is compatible with a NOAEL of 125 mg/kg/day and a LOAEL of 250 mg/kg/day for death in mice. 

The evaluation of dose-response relationships includes the identification of effective dose levels as well as doses that are associated with low or no increased incidence of adverse effects compared with controls. Many studies identify either the lowest dose causing an adverse effect (lowest-observed-adverse-effect level, or LOAEL) or the no-observed-adverse-effect level (NOAEL) (Calabrese Baldwin,... 

Mathematical modelling of the dose-response relationship is an alternative approach to quantify the estimated response within the experimental range. This approach can be used to determine the BMD or benchmark concentration (BMC) for inhalation exposure, which can be used in place of the LOAEL or NOAEL (Crump, 1984). The BMD (used here for either BMD or BMC) is defined as the lower confidence limit on a dose that produces a particular level of response (e.g., 1%, 5%, 10%) and has several advantages over the LOAEL or NOAEL (Kimmel Gaylor, 1988 Kimmel, 1990 USEPA, 1995 IPCS, 1999). For example, (1) the BMD approach uses all of the data in fitting a model instead of only data indicating the LOAEL or NOAEL (2) by fitting all of the data, the BMD approach takes into account the slope of the dose-response curve (3) the BMD takes into account variability in the data and (4) the BMD is not limited to one experimental dose. Calculation and use of the BMD approach are described in a US EPA... 

Although dose-response assessments for deterministic and stochastic effects are discussed separately in this Report, it should be appreciated that many of the concepts discussed in Section 3.2.1.2 for substances that cause deterministic effects apply to substances that cause stochastic effects as well. The processes of hazard identification, including identification of the critical response, and development of data on dose-response based on studies in humans or animals are common to both types of substances. Based on the dose-response data, a NOAEL or a LOAEL can be established based on the limited ability of any study to detect statistically significant increases in responses in exposed populations compared with controls, even though the dose-response relationship is assumed not to have a threshold. Because of the assumed form of the dose-response relationship, however, NOAEL or LOAEL is not normally used as a point of departure to establish safe levels of exposure to substances causing stochastic effects. This is in contrast to the common practice for substances causing deterministic effects of establishing safe levels of exposure, such as RfDs, based on NOAEL or LOAEL (or the benchmark dose) and the use of safety and uncertainty factors. 

Once an assessment has determined that the data indicate human risk potential, the next step is to perform a quantitative evaluation. Here, dose-response data from human and animal reproductive and developmental toxicity studies are analyzed to select LOAELs and NOAELs or to calculate a BMD. The assessment should use quantitative human dose-response data if the data span a sufficient range of exposure. Because data on human dose-response relationships are rarely available, the dose-response evaluation is usually based on an assessment of data from tests performed in experimental animals. 

Because the literature describes several limitations in the use of NOAELs (Gaylor 1983 Crump 1984 Kimmel and Gaylor 1988), the evaluative process considers other methods for expressing quantitative dose-response evaluations. In particular, the BMD approach originally proposed by Crump (1984) is used to model data in the observed range. That approach was recently endorsed for use in quantitative risk assessment for developmental toxicity and other noncancer health effects (Barnes et al. 1995). The BMD can be useful for interpreting dose-response relationships because it accounts for all the data and, unlike the determination of the NOAEL or LOAEL, is not limited to the doses used in the experiment. The BMD approach is especially helpful when a NOAEL is not available because it makes the use of a default uncertainty factor for LOAEL to NOAEL extrapolation unnecessary. 

ORNL noted that plasma-ChE values in male rats provided the least variable indicator of the lowest-observed-adverse-effect level (LOAEL) and NOAEL for GA and that there was evidence (based on mean plasma-ChE values) of a dose-response relationship. Therefore, ORNL used that data to determine the LOAEL and NOAEL for ChE inhibition by GA. ORNL considered 56.25 g/kg per day to be the LOAEL because of the significant reduction in plasma-ChE concentrations observed in male rats at this dose (relative to controls and baseline values). Because of the lack of consistent change in plasma- and RBC-AChE values (relative to controls and baseline values), ORNL considered the low dose of 28.13 A[Pg.43]

The critical study (Bucci and Parker 1992) involved a relevant route of exposure (oral) for determining an RfD. Rats were administered GB by oral gavage, a route of administration that exaggerates the exposure that would normally occur from methods resulting in a slower rate of delivery (e.g., in feed or water). However, the study was subchronic in duration (13 weeks) rather than chronic (104 weeks), and ChE measurements varied and did not show a consistent dose-response relationship across ChE types and genders. Thus, the subcommittee believes that the study was too short in duration and that the results were too variable to form an ideal basis for determining a LOAEL. In addition, the methods used to measure ChE were not ideal (see Appendix G). However, in the absence of other well-conducted studies, the subcommittee agrees with ORNL that the study by Bucci and Parker (1992) is the most appropriate of the available studies for derivation of the RfD for GB. 

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