Extrapolation in human health hazard characterization: a probabilistic approach (original) (raw)
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Regulatory Toxicology and Pharmacology, 2016
The purpose of this paper is to describe the use of toxicokinetic (TK) and toxicodynamic (TD) data in setting acceptable daily exposure (ADE) values and occupational exposure limits (OELs). Use of TK data can provide a more robust exposure limit based on a rigorous evaluation of systemic internal dose. Bioavailability data assist in extrapolating across different routes of exposure to be protective for multiple routes of exposure. Bioaccumulation data enable extrapolation to chronic exposures when the point of departure (PoD) is from a short-term critical study. Applied in the context of chemical-specific adjustment factors (CSAFs), TK data partially replace traditional default adjustment factors for interspecies extrapolation (extrapolation from studies conducted in animals to humans) and intraspecies variability (to account for human population variability). Default adjustments of 10-fold each for interspecies and intraspecies extrapolation are recommended in several guidelines, although some organization recommend other values. Such default factors may overestimate variability for many APIs, while not being sufficiently protective for variability with other APIs. For this reason, the use of chemical specific TK and TD data is preferred. Making full use of existing TK and TD data reduces underlying uncertainties, increases transparency, and ensures that resulting ADEs reflect the best available science.
Risk and Exposure Assessment from Toxic Chemicals
As a result of the foregoing discussion, the traditional approach in risk analysis that follows is recommended: An effect is only taken for granted if the deviation is significantly larger than expected from random distribution or from comparison with control populations. It is better to incorporate conservative judgments into the risk assessment methods than to change the burden of proof if the concern is to avoid underestimation of risks. In addition, special studies on selected populations may reveal significant effects that might be used as yardsticks for regulating the risk for the general public.
Risk and exposure assessment for toxic chemicals
1991
As a result of the foregoing discussion, the traditional approach in risk analysis that follows is recommended: An effect is only taken for granted if the deviation is significantly larger than expected from random distribution or from comparison with control populations. It is better to incorporate conservative judgments into the risk assessment methods than to change the burden of proof if the concern is to avoid underestimation of risks. In addition, special studies on selected populations may reveal significant effects that might be used as yardsticks for regulating the risk for the general public.
Regulatory toxicology and pharmacology : RTP, 2014
In toxicity testing the oral route is in general the first choice. Often, appropriate inhalation and dermal toxicity data are absent. Risk assessment for these latter routes usually has to rely on route-to-route extrapolation starting from oral toxicity data. Although it is generally recognized that the uncertainties involved are (too) large, route-to-route extrapolation is applied in many cases because of a strong need of an assessment of risks linked to a given exposure scenario. For an adequate route-to-route extrapolation the availability of at least some basic toxicokinetic data is a pre-requisite. These toxicokinetic data include all phases of kinetics, from absorption (both absorbed fraction and absorption rate for both the starting route and route of interest) via distribution and biotransformation to excretion. However, in practice only differences in absorption between the different routes are accounted for. The present paper demonstrates the necessity of route-specific ab...
International Journal of Hygiene and Environmental Health, 2012
a b s t r a c t REACH requires health risk management for workers and the general population and introduced the concept of Derived No-Effect Level (DNEL). DNELs must be derived for all substances that are classified as hazardous. In analogy to other health-risk based guidance values, such as reference doses (RfDs) and tolerable daily intakes (TDIs), risk to health is considered negligible if the actual exposure is less than the DNEL. Exposure assessment is relatively simple for occupational situations but more complex for the general public, in which exposure may occur via multiple pathways, routes, and media. For such complex or partially defined exposure scenarios, human biomonitoring (HBM) gives a snapshot of the internal or absorbed dose of a chemical and is often the most reliable exposure assessment methodology. For human risk management, HBM data can be interpreted using the recently developed concept of Biomonitoring Equivalents (BEs). Basically, a BE translates an established reference value into a biomarker concentration using toxicokinetic data. If the results of an exposure assessment using HBM indicate that the levels measured are below the DNEL-based BE (BE DNEL ), it would indicate that the combined exposure via all potential exposure routes is unlikely to pose a risk to human health and that health risk management measures might not be needed. Hence, BEs do not challenge existing risk assessments but rather build upon them to help risk management, the ultimate goal of any risk assessment. A challenge in implementing this approach forms the limited availability of toxicokinetic information for many substances. However, methodologies such as generic physiologically based toxicokinetic models, which allow estimation of biomarker concentrations based on physicochemical properties, are being developed for less data-rich chemicals. Acceptance of the use of BE by regulatory authorities will allow initial screening of population exposure to chemicals to identify those chemicals requiring more detailed risk and exposure assessment, assisting in priority setting and ultimately leading to improved product stewardship and risk management.
On the incorporation of chemical-specific information in risk assessment
Toxicology Letters, 2008
This paper describes the evolution of chemical risk assessment from its early dependence on generic default approaches to the current situation in which mechanistic and biokinetic data are routinely incorporated to support a more chemical-specific approach. Two methodologies that have played an important role in this evolution are described: mode-of-action evaluation and physiologically based biokinetic (PBBK) modelling. When used together, these techniques greatly increase the opportunity for the incorporation of biokinetic and mechanistic data in risk assessment. The resulting risk assessment approaches are more appropriately tailored to the specific chemical and are more likely to provide an accurate assessment of the potential hazards associated with human exposures. The appropriate application of PBBK models in risk assessment demands well-formulated statements about the chemical mode of action. It is this requirement for an explicit, mechanistic hypothesis that gives biologically motivated models their power, but at the same time serves as the greatest impediment to the acceptance of a chemical-specific risk assessment approach by regulators. The chief impediment to the regulatory acceptance and application of PBBK models in risk assessment is concern about uncertainties associated with their use. To some extent such concerns can be addressed by the development of generally accepted approaches for model evaluation and quantitative uncertainty analysis. In order to assure the protection of public health while limiting the economic and social consequences of over-regulation, greater dialogue between researchers and regulators is crucially needed to foster an increased use of emerging scientific information and innovative methods in chemical risk assessments.