Key event-informed risk models for benzene-induced acute myeloid leukaemia

Area of Science:

• Toxicology
• Occupational Health
• Risk Assessment

Background:

• Occupational benzene exposure, particularly at 10 ppm or higher, is linked to increased acute myeloid leukemia (AML) risk.
• AML development involves early key events like hematotoxicity and genotoxicity, observable in exposed workers.
• Preventing these early events could mitigate AML morbidity and mortality.

Purpose of the Study:

• To propose and describe two novel approaches for modifying quantitative risk models.
• To incorporate mechanistic information (mode of action) into risk assessment for benzene-induced AML.
• To refine risk predictions at lower exposure levels by considering early toxicity indicators.

Main Methods:

• Developed two risk model modification approaches: sub-linear and segmented linear risk increases below key event thresholds.
• Maintained a linear AML mortality risk increase starting at 2 ppm, the identified LOAEC for hemato- and genotoxicity.
• Applied continuously decreasing slope and segmented modification in slope models for exposures below 2 ppm.

Main Results:

• The proposed methods allow for the incorporation of mode of action information into quantitative risk models.
• Two distinct approaches (continuously decreasing slope and segmented modification) were detailed for risk modeling below the LOAEC.
• These approaches offer enhanced flexibility in developing and selecting appropriate risk models.

Conclusions:

• Incorporating key event information, such as hematotoxicity and genotoxicity, can significantly improve benzene risk models.
• The described sub-linear and segmented linear approaches provide a framework for more accurate risk assessment at lower exposure levels.
• These refined risk models can better inform occupational health policies and protective measures against benzene-related AML.