Modernizing problem formulation for risk assessment necessitates articulation of mode of action.
The process of scientific hypothesis formulation affects the experimental designs, methods and interpretations applied, but to be testable, the hypotheses posed must conform to the state of scientific knowledge and available technology. An analogous situation exists in risk assessment, where the questions addressed are typically articulated in the problem formulation phase. Decades ago, regulatory agencies couched problem formulation according to the questions answerable by the science of the day. As regulatory requirements for risk assessment became codified, so too did the rudiments of problem formulation. Unfortunately, codifying problem formulation prevented it from evolving to keep pace with scientific advancements. Today's more advanced science is not always being used effectively and efficiently in risk assessment because the risk assessment problem formulation step still typically poses antiquated questions. Problem formulation needs to be improved so that modern science can inform risk considerations. Based on recent developments in the Human Relevance Framework and using well-studied example chemicals - chloroform and carbon tetrachloride - an approach is proposed for focusing problem formulation on human-relevant hypotheses. We contend that modernizing problem formulation in this way will make risk assessment more scientifically accurate, more practical, and more relevant for protecting human health and the environment.
Applied Pharmacology & Toxicology, Inc., 2250 NW 24th Ave, Gainesville, FL 32605, USA; C.E.H.T., University of Florida, Dept. of Physiological Sciences, Gainesville, FL 32610, USA. Electronic address: cjborgert@apt-pharmatox.com.
Christopher J
CJ
Borgert
American Chemistry Council, 700 Second Street, NE, Washington, DC 20002, USA. Electronic address: kimberly_wise@americanchemistry.com.
Kimberly
K
Wise
American Chemistry Council, 700 Second Street, NE, Washington, DC 20002, USA. Electronic address: rick_becker@americanchemistry.com.
Richard A
RA
Becker
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002725:Chloroform / Q000633:toxicity; D006801:Humans; D012107:Research Design; D018570:Risk Assessment / Q000379:methods*; D012922:Social Change
D002725:Chloroform; D002251:Carbon Tetrachloride
Cancer classification; Carbon tetrachloride; Chloroform; Dose response; Hazard identification; Human health risk assessment; Mode of action; Problem formulation; Threshold; Weight of evidence