Time to emesis was used by previous authors to reconstruct the radiation dose that was received. In this work we emphasize the uncertainty
associated with this measure. We have provided quantitative estimates of the quality of the dose prediction through the relative standard error, confidence interval and a ROC curve. As shown in our analysis, the dose assessment based on time to emesis is imprecise, with a standard error of approximately 200% and a 95% confidence interval of
is the dose estimate. Our accuracy assessment is based on the normal/Gaussian distribution. While this assumption apparently does not apply to the original data due to skewness and heteroscedasticity, the log transformation alleviates this negative feature of the data and makes the normal assumption much more appropriate.
Computation of sensitivity and specificity is an important aspect of dose estimation, especially when considering use of the technique for triage, or screening, of potentially irradiated populations. For example, if one wants to detect 66% of the population who received 2 Gy or more, the time-to-emesis discriminant value should be less than 2 h. This criterion comes with the price of including 14% of the population who received less than 2 Gy but will have vomited within 2 h. If sensitivity is chosen to be 86%, then 4 h to emesis should be used, but this would come with a 46% false positive rate. For both cases, the potential number of false positive detections may swamp the medical care infrastructure, effectively rendering the technique impractical.
These analyses are based on the assumption that the available data are complete and are applicable to the situation where they are to be applied, i.e., to an incident involving large numbers of people such as the detonation of an improvised nuclear device with acute exposures from prompt radiation or transient heavy fallout. There are, however, several additional potential sources of uncertainty that should be considered with the use of these data for dose reconstruction based on time to emesis. All of these additional considerations increase the uncertainties calculated in the previous sections.
A substantial limitation of our analysis is that while it uses the only extensive data set that is available, the quality of the data is quite suboptimal and may be a source of the large standard error for dose prediction. More data on time to emesis are needed to make our assessment more precise. The calculations of uncertainties in the estimates of dose from time to vomiting have an implied assumption that there is no measurement error of the onset of time of vomiting in the data sets, and therefore the observed uncertainties reflect the biological variability in time to emesis. These assumptions are certainly not valid for the exposures at Chernobyl, which comprise the majority of the data points (84 of 108). The doses at Chernobyl are based on a combination of measurements and reconstruction, and it is widely recognized that these have a large degree of uncertainty. Also, the doses were delivered at varying dose rates over varying periods, which modifies the biological consequences of the radiation exposure and probably affects the tendency to vomit. The uncertainties in the data on time of onset of vomiting also are unknown but are probably fairly large, in view of the uncertainties that are acknowledged on other aspects of the personal records of the individuals involved in the accident.
The situations from which these data are obtained have several aspects that are likely to be quite different from the situations in which they are to be applied. The majority of the data points are from Chernobyl, where the individuals were first responders and early clean-up workers with minimal training in the hazards of the event. They generally received their doses over a fairly long period (about 24 h in many cases), and many of the individuals also had substantial radiation doses to the skin from particulates that were not removed promptly; both of these factors are likely to have altered the physiological responses to the radiation exposure, including the tendency to vomit. There were also simultaneous exposures to other environmental toxins generated in the accident. These potentially confounding factors were not as uniformly present in the other accidents, but the conditions may also have varied from the types of applications for which the guidelines are likely to be applied. While the data from the 108 individuals may be the best that we have, one might argue that this does not make them applicable for the very different situation in which they are proposed to be used as part of the decision-making process.
Importantly, the data used for the analyses also did not consider individuals who did not vomit. Such individuals, regardless of dose, would be excluded from the medical system if time to emesis was the sole criterion and would tend to be excluded if time to emesis was a major but not exclusive criterion. Waselenko et al
) have published a table that provides data (source not given) that estimates the percentage of subjects vomiting at different dose levels. This varies from 19% at 1 Gy to >94% at 6 Gy or higher.
Perhaps an even more important factor is the potential effect of panic and fright in the exposed population. The populations that would be involved in an incident in the future are likely to have much more knowledge of the effects of radiation than did those exposed at Chernobyl. This may significantly enhance the probability of psychogenically induced emesis, especially if there are many cases of true radiation-induced emesis. The contagious nature of emesis is well documented. While such possibilities are mentioned in some of the documents for guidance, these are not factored in when providing the guidance based on time to emesis.
There is also the potential for terrorists to exploit knowledge of the guidelines using time to emesis. For some types of devices, especially a radiation dispersal device, it would be feasible for the terrorists to include emetic agents within the device.
The concern for having false positives (i.e., individuals who have a short time to emesis but who did not receive high doses of radiation) potentially extends beyond the problems of overwhelming the medical response system. There is considerable effort and some indication of success in the development of radiation-mitigating drugs. To the extent that these are developed successfully and administered as soon after exposure as possible (which is very likely) and have potential toxicity (which also is very likely), the potential for harm from false positives could increase substantially.
In view of the uncertainties associated with the use of time to emesis, what might be the most appropriate way to use the parameter in a situation that requires triage of a large population? We suggest that, in view of its simplicity and clear end point, in spite of its limitations, it has potential for some utility. To use it effectively, however, three additional elements should be taken into consideration:
- The managers of the events need to be fully informed as to the statistical uncertainties associated with the use of any end points based on the time to emesis, so that they are aware of the likely false positive and false negative assignments of dose. In addition, the managers also should be informed of the factors that increase the uncertainties beyond those of the calculated uncertainties, including that fact that some individuals who receive clinically significant doses may not vomit at all and that some who vomit may do so as a result of psychogenic factors.
- There should be full use of other potential biodosimetric assays. While the biological assays such as cytogenetic analyses and rates of depletion of lymphocytes have been useful in the assessment of incidents involving small numbers of individuals, they would be very difficult to use in a large event. There are some promising developments of variations on these and on other biologically based assays that may be applicable in the field, and when available these should be used, even though they also may have considerable uncertainties (17). There also are some promising physically based biodosimetric approaches based on electron paramagnetic resonance measurements of teeth in situ and clippings of fingernails.
- The data for time to emesis should be considered as only one of the factors in assigning a dose, and all other clinical and dosimetric information that is available should also be used. While this point is often stressed in guidance documents, we suggest that more emphasis be placed on the consideration of the uncertainties associated with the use of each parameter. As indicated in this paper, this has not been the case previously in regard to time to emesis as an end point, and to a considerable extent, the same consideration applies to the other parameters as well.