Risk assessment LOAEL

For acute toxicity, corrosivity and skin and eye irritation, values for the NOEL (or NOAEL or LOAEL) are not derived. Therefore, the only option is to determine whether the substance has an inherent capacity to cause such effects and to make a qualitative risk assessment to evaluate the likelihood of an adverse effect occurring in use. 

Mutagenicity and carcinogenicity are generally considered to be non-threshold effects, unless a non-genotoxic mechanism can be established with a NOEL (or NOAEL or LOAEL). Risk assessment is based on establishing whether exposure is prevented. A similar process of preventing exposure also applies for skin and respiratory sensitisers, since there is no means of identifying a dose or concentration below which adverse effects will not occur in someone already sensitised to a particular substance. 

The subjects of NOAELs and LOAELs are critical to the risk assessment process, and we shall he referring to them throughout the hook. 

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. 

Hazard characterization, also known as dose-response assessment, is the second stage in hazard assessment, and the second step in the process of risk assessment. At this step, the No-Observed-Adverse-Effect Level (NOAEL) and the Lowest-Observed-Adverse-Effect Level (LOAEL) are derived for the observed effects, where possible and appropriate. 

The concept of the Benchmark Dose (BMD), a benchmark is a point of reference for a measurement, in health risk assessment of chemicals was first mentioned by Crump (1984) as an alternative to the NOAEL and LOAEL for noncancer health effects in the derivation of the ADI/TDI these terms are addressed in detail in Chapter 5. The BMD approach provides a more quantitative alternative to the dose-response assessment than the NOAEL/LOAEL approach. The goal of the BMD approach is to define a starting point of depariure (POD) for the establishment of a tolerable exposure level (e.g., ADI/TDI) that is more independent of the study design. In this respect, the BMD approach is not... 

The adverse reproductive effects are considered as being threshold effects, i.e., effects for which there are expected to be a threshold of substance concentration below which the effects will not be manifested. For the hazard and risk assessment, it is important to identify those dose levels at which adverse reproductive effects are observed, and the dose level at which adverse reproductive effects are not observed, i.e., to derive a NOAEL for reproductive toxicity. Crucial in the derivation of the NOAEL and/or LOAEL, is the definition of adverse effects (Section 4.2.2). In the derivation of the NOAEL and/or LOAEL, a number of factors need to be considered these issues are addressed in detail in Sections 4.2.3 and 4.2.4. An alternative approach to the derivation of the... 

The assessment factors generally apphed in the estabhshment of a tolerable intake from the NOAEL, or LOAEL, for the critical effect(s) are apphed in order to compensate for rmcertainties inherent to extrapolation of experimental animals data to a given human situation, and for rmcertainties in the toxicological database, i.e., in cases where the substance-specific knowledge required for risk assessment is not available. As a consequence of the variabihty in the extent and nature of different databases for chemical substances, the range of assessment factors apphed in the establishment of a tolerable intake has been wide (1-10,000), although a value of 100 has been used most often. An overview of different approaches in using assessment factors, historically and currently, is provided in Section 5.2. 

In conclusion, the traditional assessment factors (interspecies, intraspecies, subchronic-to-chronic, LOAEL-to-NOAEL, and database-deficiency) are considered to cover the concerns and uncertainties for children adequately, i.e., no children-specific assessment factor is needed when setting tolerable intakes. However, it is recommended to perform children-specific risk assessments for chemical substances in products and foods intended for children, based on specific exposure assessments for children. 

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. 

The EU TGD (EC 2003) recognized that the NOAEL is not very accurate with respect to the degree to which it corresponds with the (unknown) true NAEL. In the case of a steep curve the derived NOAEL can be considered as more reliable (the greater the slope, the greater the reduction in response to reduced doses) in the case of a shallow curve, the uncertainty in the derived NOAEL may be higher and this has to be taken into account in the assessment. If a LOAEL has to be used in the assessment, then this value can only be considered reliable in the case of a very steep curve. According to KEMI (2003), extrapolation factors of between 3-5 are used for LOAEL-to-NOAEL extrapolation without any scientific basis in risk assessment reports of existing substances within the European Union. 

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. 

An important parameter in the risk assessment of hazardous wastes is the no-effect level to which a population may be exposed. This level, defined as the no observed effect level (NOEL), is difficult to measure and also difficult to define accurately. Its values are based on epidemiological data and controlled animal experiments designed to determine the highest dose that wiU not produce an adverse effect. The no observed adverse effect level (NOAEL) is a variant of the NOEL in that it classifies only toxicological effects. Other measures related to the NOEL and the NOAEL are the LOEL lowest observed effect level) and LOAEL lowest observed adverse effect level), a stricter version of the LOEL. 

Benchmark Dose (BMD) modeling is an alternative method to the NOAEL/ LOAEL approach (Cmmp, 1984 Dourson et al., 1985 Barnes et al., 1995 U.S. EPA, 2000a). The method fits flexible mathematical models to the dose-response data and then determines the dose associated with a specified incidence of the adverse effects. Once this dose is estimated, then an RfD is estimated with the use of one or more uncertainty factors or Chemical Specific Adjustment Factors (CSAF) as described above. Advantages over the NOAEL/LOAEL approach include (1) the BMD is not limited to the tested doses (2) a BMD can be calculated even when the study does not identify a NOAEL and (3) unlike the NOAEL approach, the BMD approach accounts for the statistical power of the study. Numerous examples of BMD use in the dose-response assessment part of the risk assessment process are available on the U.S. EPA s Integrated Risk Information System (IRIS) (2004b). 

The initial process in the application of toxicity (dose-response) data in risk assessment is the extrapolation of findings to establish acceptable levels (AL) of human exposure. These levels may be reference values (inhalation reference concentrations, RfC or oral reference doses, RfD), minimal risk levels (MRL) values, occupational exposure limits, and so on. When the toxicity data are derived from animals, the lowest dose representing the NOAEL (preferably) or the LOAEL defines the point of departure (POD). In setting human RfD, RfC, or MRL values, the POD requires several extrapolations (see [13] and revisions). Extrapolations are often made for interspecies differences, intraspecies variability, duration of exposure, and effect level. Each area is generally addressed by applying a respective uncertainty factor having a default value of 10 their multiplicative value is called the composite uncertainty factor (UF). The UF is mathematically combined with the dose at the POD to determine the reference value ... 

Until better statistical methods become available, risk assessment for MeHg should be based on benchmark dose calculations rather than NOAELs or LOAELs. 

The US EPA has developed so-called Reference Doses (RfD) (US EPA 1997, Vol. V). For a risk assessment of inorganic ionic mercury, it ivas concluded that the critical (= most sensitive adverse) effect is the formation of autoimmune glomerulonephritis. The production and deposition of IgG antibodies to the glomerular basement membrane was considered the first step in the formation of this (for details, see Section 17.6.6). On the basis of three animal experiments on this effect with Brown-Norway rats, lifetime LOAEL levels of 0.23 to 0.63 mg Hg kg per day were calculated, and from these an RfD for humans of 0.3 jg kg body weight per day was derived. This concerned an overall uncertainty factor of 1000 (10 from subchronic to chronic exposurexlO from LOAEL to NOAELxlO both from animal to humans and sensitive populations). 

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