Facilitation of risk assessment with evidence-based methods - A framework for use of systematic mapping and systematic reviews in determining hazard, developing toxicity values, and characterizing uncertainty.

Systematic review tools and approaches developed for clinical medicine are often difficult to apply "off the shelf" in order to meet the needs of chemical risk assessments. To address such, we propose an approach that can be used by practitioners for using evidence-based methods to facilitate the risk assessment process. The framework builds on and combines efforts conducted to date by a number of agencies and researchers; the novelty is in combining these efforts with a practical understanding of risk assessment, and translating such into a 'step-by-step' guide. The approach relies on three key components: problem formulation, systematic evidence mapping, and systematic review, applied using a stepwise approach. Unique to this framework is the consideration of exposure in selecting, prioritizing, and evaluating data (e.g., dose-relevance, routes of exposure, etc.). Using the proposed step-by-step process, critical appraisal of individual studies (e.g., formal and structured assessment of both relevance and reliability) and integration efforts are considered in context of specified risk assessment objectives (e.g., mode of action, dose-response) as well as chemical-specific considerations. The resulting framework provides a logical approach of how evidence-based methods can be used to facilitate risk assessment, and elevates the use of systematic methods beyond hazard identification to directly facilitating transparent and objective selection of candidate studies and/or datasets used to quantitatively characterize risk, and to better use the underlying process to inform the approaches used to develop toxicity values.

Improving risk assessment approaches for chemicals with both endogenous and exogenous exposures.

To conduct risk assessments of exogenous chemicals for which there are also endogenous exposures, knowledge of the chemistry and biology of both types of exposures needs to be integrated into problem formulation and carried through to risk characterization. This issue is framed in a risk assessment context, highlighting the importance of quantifying increments of dose from all sources of the same or similar chemicals interacting with biological targets; understanding the influence of endogenous chemical concentrations on disease risk; and assessing total dose to targets in evaluating risk from incremental environmental exposures. Examples of recent assessments illustrate the importance of addressing this issue. Evaluations of data on blood or organ concentrations of ammonia, methanol, formaldehyde, acetaldehyde, and three gaseous signaling molecules (hydrogen sulfide, carbon monoxide, and nitric oxide) provide examples where current data are already informing perspectives on relative exposures at the portal of entry and systemically. To facilitate quality risk assessments of exogenous chemicals with endogenous exposures, a series of specific questions are presented that need to be addressed in systematic review to enhance problem formulation, improve the development of holistic conceptual models, and to facilitate the identification of priority data needs for improving risk assessments.

Development of a cancer-based chronic inhalation reference value for hexavalent chromium based on a nonlinear-threshold carcinogenic assessment.

The carcinogenicity of hexavalent chromium(CrVI) is of significant interest to regulatory agencies for the protection of public health and to industry. Additionally, the mode of action (MOA) and conditions under which CrVI may induce carcinogenicity (e.g., reductive capacity considerations) have recently been the subject of significant scientific debate. Epidemiological data supported by data relevant to the carcinogenic MOA support considering nonlinear-threshold carcinogenic assessments for comparison to default linear low-dose extrapolation approaches. This study reviews epidemiological studies available in the scientific literature and conducts additional statistical dose-response analyses to identify potential carcinogenic thresholds and points of departure (PODs) in the context of supportive MOA information for a nonlinear-threshold inhalation carcinogenic assessment. Dosimetric adjustments and application of appropriate uncertainty factors (total UF of 30) to the selected cumulative exposure POD results in a cancer-based chronic inhalation reference value (ReV) of 0.24 µgCrVI/m(3). This chronic ReV is 300 times higher than the 1 in 100,000 excess cancer risk air concentration of 8E-04 µg/m(3) based on USEPA's unit risk factor.