Table 1.

Key risk assessment methodologies for the next generation of risk science: comparison of current and NexGen approaches.

Methodology	Current approach	NexGen approach
Hazard identification, dose–response assessment, and exposure assessment
Hazard identification	Based largely on animal toxicity testing, mainly in rodent species.	Based primarily on in vitro testing in human cells, and computational methods in biology and toxicology.
Dose–response assessment	Empirical or biologically based models describe apical end points, and determine an appropriate point of departure (such as the benchmark dose) for establishing a reference dose.	Computational systems biology pathway models describe dose–response relationships for pathway perturbations, reflecting dose-dependent transitions throughout the dose range of interest.
Dose and species extrapolation	Dose and species extrapolation translate animal test results to humans.	Cellular assays provide direct measures of toxicity pathway perturbations in humans. In vitro to in vivo extrapolation techniques and pathway modeling calibrate in vitro and in vivo exposures. Sensitive in vitro tests are used to evaluate risk directly at environmental exposure levels.
Exposure assessment	Estimates of human exposure based largely on measurements in environmental media (air, food, water, soil).	Expanded use of high throughput biomonitoring data reflecting critical toxicity pathway perturbations.
Characterization of risk and uncertainty
Adversity	Apical outcomes in mammalian systems, or precursors to these outcomes, generally serve as the basis for risk assessment.	In vitro assays identify critical toxicity pathway perturbations, which serve as the basis for risk assessment, even in the absence of a direct link with an apical outcome.
Variability	Adjustment factors used in establishing reference doses account for interindividual variability in pharmacokinetics and pharmacodynamics. Variability in exposure is also taken into account.	Variability in biological response is characterized through the use of a diverse range of human cell lines. Dosimetry models link variation in human exposure with corresponding in vitro doses.
Life stage and susceptible populations	Life stage, genetics, and socioeconomic and lifestyle factors determine susceptible population groups.	Molecular and genetic epidemiology defines susceptible populations in terms of critical pathway perturbations.
Mixtures and multiple stressors	Common experimental protocols include testing of mixtures and factorial experiments with joint exposures. However, the number of such studies has been limited because of cost and complexity of experimental design.	Cost-effective high throughput technologies permit expanded testing of mixtures and multiple stressors.
Uncertainty analysis	Uncertainty considerations include species differences in susceptibility, low-dose and route-to-route extrapolation, and exposure ascertainment.	Probabilistic risk assessments characterize overall uncertainty, and identify the most important sources of uncertainty that guide value-of-information decisions.