Risk assessment NOAEL

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. 

For all toxic effects other than carcinogenicity, a threshold in the dose-response curve is assumed. The lowest NOAEL from all available studies is assumed to be the approximate threshold for the groups of subjects (humans or animals) in which toxicity data were collected. Alternatively, a benchmark dose (BMD) may be estimated from the observed dose-response curve, and used as the point-of-departure for risk assessment (see below and Box). 

The risk assessment comprises an effect assessment (hazard identification and hazard characterization) and an exposure assessment. The principles for the effect assessment of the active substances are in principle similar to those for existing and new chemicals and are addressed in detail in Chapter 4. Based on the outcome of the effect assessment, an Acceptable Daily Intake (ADI) and an Acceptable Operator Exposure Level (AOEL) are derived, usually from the NOAEL by applying an overall assessment factor addressing differences between experimental effect assessment data (usually from animal studies) and the real human exposure situation, taking into account variability and uncertainty for further details the reader is referred to Chapter 5. As a part of the effect assessment, classification and labeling of the active substance according to the criteria laid down in Directive 67/548/EEC (EEC 1967) is also addressed (Section 2.4.1.8). 

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... 

Internationally, the BMD approach is used by the US-EPA to derive health-based limit values (US-EPA 2007a). Within the OECD (OECD 2000) and the European Union (EC 2003), the BMD approach is also mentioned as an alternative to the traditional NOAEL approach in health risk assessment but is not implemented in regulatory toxicology within the European Union. 

Acute toxic 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 signs of acute toxicity are observed, and the dose level at which acute toxicity is not observed, i.e., to derive a NOAEL for acute toxicity. However, it should be noted that a NOAEL is usually not derived in the classic acute toxicity smdies, partly because of the limitations in smdy design. 

If it is possible to identify a NOAEL from well-reported and reliable human smdies, this value may be used preferentially in the risk assessment. However, it is expected that this will rarely be the case. 

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. 

Risk assessments are usually based on data from studies in animals of similar age. In addition, the animals are initially healthy and are fed with the same feed, etc. The NOAEL from animal smdies is extrapolated to a tolerable intake that is considered to be without appreciable health risk for the general population. This raises the questions whether it is possible to generalize to the average human population or whether there is any particular vulnerable subpopulation that should be taken into consideration in the risk assessment. 

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. 

FIGURE S.6 Schematic illustration of the traditional setting of an acceptable level of exposure (ADI) by dividing the NOAEL from an animal study by an assessment factor (AF). The two dose-response relationships have identical NOAEL. If a uniform assessment factor is applied, there will be an adequate MOS at the ADI for effect b but not for effect a. (Modified from KEMI, Human health risk assessment. Proposals for the use of assessment (uncertainty) factors. Application to risk assessment for plant protection products, industrial chemicals and biocidal products within the European Union. Report No. 1/03, Solna, Sweden, 2003. 

The question of an extra assessment factor in the hazard and risk assessment for chemicals of concern for children is specifically addressed in Section 5.2.1.13. The U.S. Food Quality Protection Act (FQPA) (US-EPA 1996) directed the US-EPA to apply an extra safety factor of 10 in assessing the risks of pesticides to infants and children. The US-EPA (2002) noted the overlap of areas covered by the FQPA factor and those addressed by the traditional UFs, and it was concluded that an additional UF (children-specific) is not needed in the setting of reference values because the currently available UFs (interspecies, intraspecies, LQAEL-to-NOAEL, subchronic-to-chronic, and database-deficiency) were considered sufficient to account for uncertainties in the database from which the reference values are derived. Renwick et al. (2000) concluded that the available data did not provide a scientific rationale for an additional 10-fold UF for infants and children and pointed out that when adequate reproduction, multigeneration, or developmental studies are conducted, there will be no need for an additional 10-fold factor. 

Risk characterization is thus the step in the risk assessment process where the outcome of the exposure assessment (e.g., daily intake via food and drinking water, or via inhalation of airborne substances) and the hazard (effects) assessment (e.g., NOAEL and tolerable intake) are compared. If possible, an uncertainty analysis should be carried out, which produces an estimation of the risk. Several questions should be answered before comparison of hazard and exposure is made ... 

Although the HI method is transparent, easily understandable, and directly relates to the RfD, the major disadvantage is that the RfD is not an appropriate metric to use as a POD for cumulative risk assessment, since the RfD is normally derived by using NOAELs and uncertainty factors, which are not data based, but may incorporate significant policy-driven assumptions. This issue is addressed in detail in Chapter 5. 

There are of course many mathematically complex ways to perform a risk assessment, but first key questions about the biological data must be resolved. The most sensitive endpoint must be defined along with relevant toxicity and dose-response data. A standard risk assessment approach that is often used is the so-called divide by 10 rule . Dividing the dose by 10 applies a safety factor to ensure that even the most sensitive individuals are protected. Animal studies are typically used to establish a dose-response curve and the most sensitive endpoint. From the dose-response curve a NOAEL dose or no observed adverse effect level is derived. This is the dose at which there appears to be no adverse effects in the animal studies at a particular endpoint, which could be cancer, liver damage, or a neuro-behavioral effect. This dose is then divided by 10 if the animal data are in any way thought to be inadequate. For example, there may be a great deal of variability, or there were adverse effects at the lowest dose, or there were only tests of short-term exposure to the chemical. An additional factor of 10 is used when extrapolating from animals to humans. Last, a factor of 10 is used to account for variability in the human population or to account for sensitive individuals such as children or the elderly. The final number is the reference dose (RfD) or acceptable daily intake (ADI). This process is summarized below. 

Biomarkers are used at several stages in the risk assessment process. Biomarkers of exposure are important in risk assessment, as an indication of the internal dose is necessary for the proper description of the dose-response relationship. Similarly, biomarkers of response are necessary for determination of the no observed adverse effect level (NOAEL) and the dose-response relationship (see below). Biomarkers of susceptibility may be important for identifying especially sensitive groups to estimate an uncertainty factor. 

The data so acquired is used for the risk assessment and safety evaluation of drugs prior to human exposure, for food additives before use, and for industrial and environmental chemicals. In the case of drugs, this information is essential before the drug can be administered to patients in clinical trials, and similarly, for food additives and other chemicals, it is required to set a NOAEL (see below). 

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