Advancing human health risk assessment: Integrating recent advisory committee recommendations

Abstract

Over the last dozen years, many national and international expert groups have considered specific improvements to risk assessment. Many of their stated recommendations are mutually supportive, but others appear conflicting, at least in an initial assessment. This review identifies areas of consensus and difference and recommends a practical, biology-centric course forward, which includes: (1) incorporating a clear problem formulation at the outset of the assessment with a level of complexity that is appropriate for informing the relevant risk management decision; (2) using toxicokinetics and toxicodynamic information to develop Chemical Specific Adjustment Factors (CSAF); (3) using mode of action (MOA) information and an understanding of the relevant biology as the key, central organizing principle for the risk assessment; (4) integrating MOA information into dose–response assessments using existing guidelines for non-cancer and cancer assessments; (5) using a tiered, iterative approach developed by the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) as a scientifically robust, fit-for-purpose approach for risk assessment of combined exposures (chemical mixtures); and (6) applying all of this knowledge to enable interpretation of human biomonitoring data in a risk context. While scientifically based defaults will remain important and useful when data on CSAF or MOA to refine an assessment are absent or insufficient, assessments should always strive to use these data. The use of available 21st century knowledge of biological processes, clinical findings, chemical interactions, and dose–response at the molecular, cellular, organ and organism levels will minimize the need for extrapolation and reliance on default approaches.

Whither Risk Assessment: New Challenges and Opportunities a Third of a Century After the Red Book

“…In fact, the recent findings of the NAS (17) regarding problem formulation by risk managers as a prerequisite to any risk assessment process provide an important clarification of these roles, and one practiced for some time by different government organizations. (18) …”

Cancer Biology, Toxicology and Alternative Methods Development Go Hand‐in‐Hand

“…Thus, the toxicity effects that arise following chemical or ENM exposures both cause and reflect a diseased state at subcellular, cellular and organ levels [2,4,12]. Such studies therefore serve to probe the multiple and complex means whereby detrimental effects and disease processes arise [7,9]. From technology viewpoint, studies of normal and transformed cell line models in vitro are central to both cancer biology and toxicology work, paving the way to increasing application of cell models as alternatives to animal-based experiments ( fig.…”

“…Such work includes the exploration or verification of novel or known pathways of toxicity, MoA mechanisms and in a broader sense, adverse outcome pathways (AOP) [2,4,5,[11][12][13]31,32]. Expanded testing regimes might naturally apply a wider range of cell types and assays, including the consideration of low-dose effects and application of differentiated, metabolically competent cell models [6,7,19,33,34].…”

“…A constantly increasing number of chemicals and engineered nanomaterials (ENMs) emphasize the need of applying novel tools and screening technologies outside of the standard, both lengthy and expensive, rodent toxicological tests traditionally used in such work [1][2][3][4][5][6][7][8][9][10][11][12][13]. Especially considered for the future innovation of novel ENMs, safety evaluations should be integrated proactively and efficiently already in the material and product development phase [9,12].…”

US Environmental Protection Agency's framework for human health risk assessment to inform decision making

“…EPAs efforts to advance risk assessment practice have been in parallel with many other efforts including those of the World Health Organization/International Programme on Chemical Safety, the International Life Sciences Institute and the Alliance for Risk Assessment (Pastoor et al, 2014;Dourson et al, 2013;Munns et al, 2003;Birnbaum et al, 2001).…”