ChE inhibition

The rapid growth in the use of OPs and the proliferation of new active ingredients and formulations was not without its problems. Some OPs proved to be too hazardous to operators because of very high acute toxicity. A few were found to cause delayed neurotoxicity, a condition not caused by ChE inhibition (e.g., mipafox, lepto-phos). There was also the problem of the development of resistance, for example, by... 

In California, mixer-loaders and spray applicators who work with toxicity category I and II organophosphates or N-methyl carbamates more than 30 hours per 30-day period are required to have medical supervision. Supervision consists of an interview and a medical examination to determine if a medical condition exists which would make the worker unusually susceptible to poisoning due to cholinesterase inhibition, and to caution the individual about the use of certain drugs such as the pheno-thiazine tranquilizers vdtich potentiate the effects of cholinesterase (ChE) inhibition. Two blood samples, taken several days apart, are analyzed to determine the individual s preexposure plasma and red blood cell (RBC) ChE activity (baseline value). The physician arranges a routine ChE testing program and provides for extra ChE tests should the worker be accidently exposed to OP s. If ChE activity is depressed to 50 percent of the baseline value, the physician may ask the employer to place the worker on... 

At the completion of the study, the data obtained should be evaluated in relationship to exposure (dermal and inhalation), absorption (urinary metabolites), effects (ChE inhibited), acute, chronic, and metabolic studies in laboratory animals. These findings should then be evaluated and discussed in relation to existing or proposed labeling or regulations. 

The major gap in the available information on GA is the lack of either a subchronic or a chronic oral toxicity study from which to derive the RfD. The absence of oral data could be addressed by conducting a subchronic oral toxicity study that assesses anti-ChE activity in red blood cells (RBCs) and plasma in one or preferably two species. If further research reveals that significant toxic effects can be induced by any of the nerve agents at doses below those that cause significant ChE inhibition, additional studies should be conducted to reassess the safety of the recommended RfD for GA. 

The major gap in the available information on VX is the lack of either a subchronic or a chronic oral toxicity study that demonstrates a clear dose-response relationship between VX exposure and ChE inhibition. The absence of that type of data could be addressed by conducting a... 

ORNL noted that plasma-ChE values in male rats provided the least variable indicator of the lowest-observed-adverse-effect level (LOAEL) and NOAEL for GA and that there was evidence (based on mean plasma-ChE values) of a dose-response relationship. Therefore, ORNL used that data to determine the LOAEL and NOAEL for ChE inhibition by GA. ORNL considered 56.25 g/kg per day to be the LOAEL because of the significant reduction in plasma-ChE concentrations observed in male rats at this dose (relative to controls and baseline values). Because of the lack of consistent change in plasma- and RBC-AChE values (relative to controls and baseline values), ORNL considered the low dose of 28.13 A[Pg.43]

The NOAELadj (115 pg/kg per day) used by ORNL for derivation of the RfD for GA was based on the dose that did not cause a significant depression in plasma-ChE activity in rats (Bucci et al. 1992). The subcommittee notes that ChE inhibition is typically considered a biomarker of expo... 

Although the subcommittee agrees with ORNL that ChE inhibition is a valid end point on which to base the RfD for GA, the subcommittee s confidence in the data is undermined by the increased baseline RBC-AChE concentrations, which were attributed to laboratory errors, in the critical study. Eurthermore, confidence in the calculation of an equivalent oral NOAEL from an i.p. NOAEL is diminished because data from a secondary reference (i.e., RTECS 1995) were used to determine the ratio of the oral LD50 to the i.p. LD50. The subcommittee suggests that the data be verified from the primary source and cited appropriately. 

ORNL noted that in the derivation of RfDs for other organophosphate compounds, EPA (1989, 1992) used NOAELs for ChE inhibition that... 

Provided that appropriate assays were used, the subcommittee finds no reason at this time to alter the practice of using RBC-ChE or plasma-ChE inhibition as the critical end point and agrees with ORNL that such inhibition is the best available critical noncancer end point on which to base the calculation of the RfD for GB. 

ORNL assigned a factor of 3 rather than 10 to the uncertainty factor for extrapolation from a LOAEL to a NOAEL (UFl) becanse ChE inhibition is a biomarker of exposure rather than a toxic effect. Although it could be argued that a dose of GB that significantly indnces ChE inhibition in the absence of toxic effects is indicative of a NOAEL rather than a LOAEL, the snbcommittee agrees that a factor of 3 is a conservative choice for UFl. 

The subcommittee believes that the strength of evidence for the Army s interim RfD of 2 x 10 mg/kg per day for GB is moderately good. There is a possibility that the LOAEL (0.075 mg/kg per day) used to calculate the RfD for GB is not accnrate, becanse lower doses were not tested and variability in the RBC-ChE values was considerable. The snbcommittee believes that because ChE inhibition is a biomarker of exposure rather than a toxic effect, use of this end point overestimates the oral toxicity of GB. 

The subcommittee considered other possible toxicity end points, notably neurotoxicity, associated with GD exposure. Organophosphate compounds like GD may act directly on nerve cell receptors or, by inhibiting neural AChE, interfere with neuromuscular transmission and produce delayed-onset subjunctional muscle damage. In addition, some organophosphate compounds cause a neurotoxic effect (organophosphate-induced delayed neuropathy, or OPIDN) that is not associated with ChE inhibition. Emerging research in this area might indicate alternative... 

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