Advancing human health risk assessment: integrating recent advisory committee recommendations

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.