Risk assessment threshold approaches

As scientific community has recognized that there is no identifiable threshold below which PAHs do not pose risk to humans, genotoxic and carcinogenic PAHs require the fullest possible risk assessment. Several approaches have been developed to evaluate the potencies of the components of a complex mixture of PAHs. In this work values of TEF reported by Muller which includes a assessment for dibenzo[a,l]pyrene (Bostrom et al., 2002) were used in order to calculate the TEF-adjusted concentrations (based on benzo[a]pyrene). The results of TEF djusted concentrations for 18 PAHs at the studied pre-school are presented in Table 2. 

Apart from the use of this approach to study the ecotoxicology of neurotoxic pollutants in the field, it also has potential for use during the course of environmental risk assessment. An understanding of the relationship between biomarker responses to neurotoxic compounds and effects at the population level can be gained from both field studies and the use of mesocosms and other model systems. From these it may be possible to define critical thresholds in biomarker responses of indicator species above which population effects begin to appear. In the longer term, this approach... 

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... 

In classifying waste, deterministic responses generally should be of concern only for hazardous chemicals (see Section 3.2.2.1). Therefore, the only important issue for risk assessment is the most appropriate approach to estimating thresholds for induction of responses in humans. The primary concern here is that consistent approaches should be used for all substances that induce deterministic effects. NCRP s recommendation that nominal thresholds in humans should be estimated using the benchmark dose method and a safety factor of 10 or 100, depending on whether the data were obtained in a study in humans or animals (see Section 6.1.2.1), is intended to provide consistency in estimating thresholds for all substances that cause deterministic effects. 

In many respects, the foundations and framework of the proposed risk-based hazardous waste classification system and the recommended approaches to implementation are intended to be neutral in regard to the degree of conservatism in protecting public health. With respect to calculations of risk or dose in the numerator of the risk index, important examples include (1) the recommendation that best estimates (MLEs) of probability coefficients for stochastic responses should be used for all substances that cause stochastic responses in classifying waste, rather than upper bounds (UCLs) as normally used in risk assessments for chemicals that induce stochastic effects, and (2) the recommended approach to estimating threshold doses of substances that induce deterministic effects in humans based on lower confidence limits of benchmark doses obtained from studies in humans or animals. Similarly, NCRP believes that the allowable (negligible or acceptable) risks or doses in the denominator of the risk index should be consistent with values used in health protection of the public in other routine exposure situations. NCRP does not believe that the allowable risks or doses assumed for purposes of waste classification should include margins of safety that are not applied in other situations. 

Such threshold values are often estimated using no-observed-effect concentrations or levels (NOECs or NOELs). It might be tempting to substitute the individual ECx values in the CA equation (Equation 4.2) with NOELs in order to calculate a mixture NOEL. But this would imply that all NOELs provoke the same, statistically insignificant effect that is, all of them must have been determined in an identical experimental setup (in terms of number of replicates, spacing of test concentrations, variance structure), which is hardly ever the case. Nevertheless, a range of methods, such as TEFs or TEQs (see Chapters 1 and 5), makes use of a CA-like approach and sums up NOEL-based hazard quotients. This introduces an additional source of uncertainty in the risk assessment, which is fundamentally different from the question of whether CA is an appropriate concept for the mixture of interest. 

The effects of genotoxic compounds are considered non-threshold. Thus, risk assessment for a given exposure is usually performed by a linear or sub-linear extrapolation from the high dose effects observed in animals to the lower human exposure. Since the outcome of the extrapolation depends on the model applied and extrapolation over different orders of magnitude is error prone, the European Food and Safety Authority (EFSA 2005) recommended to avoid this extrapolation and proposed the MOE approach. This approach uses the benchmark dose, or the T25 calculated from a carcinogenicity study and compares this with human exposure. A MOE of 10,000 and more is considered to be of minor concern. The advantage is that neither a debatable extrapolation from high to low doses needs to be performed nor are hypothetical cancer cases calculated. For details of the different approaches see, SCHER, SCCP, SCENIHR (2008). 

A protocol for risk assessment of unlisted migrants should be developed that is pragmatic, cost-effective and accepted by both industry and legislative authorities. In this protocol, exposure, toxicology and chemical analysis should be combined. A possible combination would be the approach described above of relating exposure to the threshold of toxicological concern (TTC) principle. This would determine the analytical boundaries for screening of... 

Two examples of alternative approaches to cancer risk assessment would be estimations based on threshold-response (EPA, 2005a) and benchmark dose modeling (EPA, 1995, 2000). As a practical matter, if the proposed basis of safety relies on a threshold or mode-of-action characterization to dismiss or mitigate animal tumor data, PDA would reconunend that the safety narrative clearly discuss the scientific rationale and present all relevant data for consideration. In the absence of adequate evidence to the contrary, PDA presumes that certain assumptions are appropriately protective of safety, namely that (i) the induction of tumors in animals is relevant to human... 

The consideration of mode of action in carcinogen risk assessment is becoming standard practice. When data are adequate to demonstrate use of the standard default low dose extrapolation models such as the linearized multistage model is not appropriate, alternate approaches, including threshold approaches are now being used. 

Dose-response assessment follows the hazard identification in the risk assessment process. In dose-response assessment, an adverse effect is presumed to either exhibit a threshold or not in the dose-response curve. Depending on the nature of this curve, different approaches are employed to estimate the risk posed by the potential toxic agent. 

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