Deriving toxicity values for organophosphate nerve agents: A position paper in support of the procedures and rationale for deriving oral RfDs for chemical warfare nerve agents

During the process of deriving oral Reference Dose (RfDs) values for chemic al warfare agents, several issues arose regarding the identification of adv erse effect levels and the application of uncertainty factors. For those ag ents that function as cholinesterase inhibitors (e.g., agents VX, GA, GB, a nd GD), these issues included the following: (1) Is the endpoint of blood c holinesterase inhibition an indicator of toxicity or a biomarker of exposur e? (2) Can an experimental animal species be more sensitive than humans, th ereby eliminating the need for an animal-to-human uncertainty factor? (3) C an the uncertainty factor that is used to extrapolate from a lowest-observe d adverse-effect-level (LOAEL) to a no-observed-adverse-effect-level (NOAEL ) be less than the default value of 10? (4) Can an oral RfD be derived from non-oral toxicity data? (5) Can an uncertainty factor of less than 10 be u sed to extrapolate from subchronic to chronic exposure (i.e., is the critic al effect adequately described by the subchronic exposure data)? (6) What c onstitutes an adequate data base for organophosphate cholinesterase inhibit ors, and what uncertainty factor should be used for an incomplete data base ? Analysis of relevant data resulted in the following selection and justifica tions of uncertainty factors. For uncertainty associated with intraspecies extrapolation (UFH), physiologic and pathologic conditions affecting cholin esterase activity levels justified maintaining a UFH of 10 for all of the n erve agents. Because available data indicated that humans tended to be more sensitive than rats regarding anticholinesterase effects, an interspecies variability (UFA) factor of 10 was retained for agents GA, GB, and GD. For agent VX, however, the available data revealed that the domestic sheep test species exhibited sensitivity equivalent to or greater than that of humans thereby justifying a UFA of 1. For uncertainties regarding extrapolation f rom subchronic-to-chronic exposure data, consideration of information on th e physiology of cholinergic systems and the available toxicity data for the nerve agents and other cholinesterase inhibitors indicated that a UFS of 3 was justified for all four of the nerve agents. For uncertainties regardin g LOAEL-to-NOAEL extrapolation (UFL), the selection of agent GB, GD, and VX doses resulting in cholinesterase inhibition in the absence of clinical si gns of toxicity (biomarker of exposure) justified this endpoint as a minima l LOAEL and a UFL of 3. For agent GA, a NOAEL was used, and therefore no UF L was required. The uncertainty factor for data base completeness (UFD),was based upon several considerations. Of primary concern was the fact that ch ronic toxicity studies are not considered an essential component of the dat a base requirements for cholinesterase inhibitors because of the unlikeliho od that the endpoint will change with an increase in exposure time beyond t hat defined as a subchronic exposure. Additionally, limited data regarding reproductive and developmental toxicity were not considered to represent cr itical toxicity endpoints for the nerve agents or cholinesterase inhibitors in general. Although the data base for agents GA, GB, and GD were lacking reproductive and developmental toxicity data to some extent, a UFD of 3 was justified for the aforementioned reasons. The data base for agent VX was c onsidered complete and a UFD of 1 was selected for development of the RfD f or this agent. A modifying factor (MF) to reflect qualitative assessment of additional uncertainties in the critical study or data base that are not a ddressed by uncertainty factors was limited to agent GA due to the route-to -route (i.e., intraperitoneal to oral) extrapolation and to insure the equi valent oral NOAEL was not overestimated. This article provides a brief overview of the nerve agents, information on cholinergic systems that is pertinent to deriving toxicity values for nerve agents and other organophosphate cholinesterase inhibitors, and a discussi on of key issues regarding the use of uncertainty factors in RfD derivation s.