that the entire mixture would be less potent than an equal exposure to the most potent component of the mixture.
PBPK modeling can aid in extrapolating exposures from animals to humans. Recent work exploring the use of fluoride ion regeneration as a dose metric that is more sensitive and less variable than changes in AChE may be useful in improving the interspecies extrapolation for CWAs as well as addressing the exposure duration extrapolation issue and should be further explored. It should be noted that a PBPK model may not be required for extrapolating a direct contact toxic response (e.g., miosis may be an example of this if direct-contact of the CWA with the eye leads to this response).
To make the ORM concept operational, the risk assessor will require robust information on response probabilities from the experimental study. For CWAs, for each critical response (e.g., miosis), access to recently generated experimental data sets and contact with investigators should be pursued to develop other response probabilities that would be needed in operational risk assessment beyond single values, such as ECt50 or EC01 (e.g., 15%, 30%, 40%).
The toxicity end point and the mechanistic basis for the end point are factors contributing to human variability. For miosis alone, variability would be determined by the chemistry and physiology of the eye. Ambient light conditions can also contribute to the variability in miosis. For systemic effects of CWAs, variability in human response can be due to differences in the kinetics of CWA uptake and metabolism or differences in sensitivity to a given tissue dose of CWA. Further characterization of the implications of human variability in response to CWAs under military conditions would be useful for ORM.
The methodology developed for deriving AEGL values for CWAs is pertinent. The generalization of Haber’s law to effects related to Cnt (ten Berge method) is a valuable contribution. The committee recommends that DOD utilize information and techniques developed for deriving AEGLs.