The Authors Reply: The N-Methylpyrrolidone Producers Group Inc. makes three major points with regard to our article.1 The NMP producers argue (1) that animal studies rarely show fetotoxicity of NMP at doses below those that also cause maternal toxicity; (2) that overexposure of the worker was not well documented; and (3) that perinatal mortality is so common that other causes besides NMP exposure should be considered for the stillbirth we reported. Our literature review found a larger number of studies reporting fetotoxicity at doses that did not produce maternal toxicity than that acknowledged by the producers' letter. In our review, the presence of maternal toxicity was the exception. Although in a few studies, fetotoxicity occurred in the setting of decreased maternal weight gain, dry skin, and bright yellow urine staining,2 in most studies fetotoxicity occurred in the absence of any reported maternal toxicity.3-7 It is also important to remember that decreased maternal weight gain should not automatically be ascribed to maternal toxicity. In one study that reported decreased maternal weight gain as the only significant purported sign of maternal toxicity, the dams in the high-dose group gained an average of 19.4 g less than those in the control group. However, the control animals had an average of 11.2 viable offspring, each weighing 3.5 g, whereas the treated group had an average of 9.3 viable offspring with a mean fetal weight of 2.8 g.2 Thus, much of the difference in weight gain between the treated and control groups may be a result of fetal loss and decreased fetal weight, not of maternal toxicity (U. Hass, letter to Donald K Milton, September 18, 1996). The NMP producers also argue that our patient could not have been overexposed to NMP. As evidence, they cite the air-sampling results reported in our article. In our report, we acknowledge that air monitoring revealed low-level exposures at the time the samples were taken. On the other hand, the air monitoring was done weeks after the reported events occurred. We report the notable fact that measurable levels of NMP were detected in the air despite the fact that the company had since eliminated hand-washing of glassware with NMP and despite the installation of two new local exhaust hoods. In addition, laboratory technique apparently varied considerably among technicians. The patient who suffered the stillbirth reportedly had numerous splashes and small spills; no such splashes or spills occurred during the period of air sampling. Finally, we felt that the appearance of symptoms consistent with solvent dermatitis and solvent toxicity after an NMP spill that the patient cleaned up by hand was an indication that our patient may have sustained a significant overexposure. In addition, although we did not have this information at the time of publication of our case report, NMP has been conclusively shown to cross the placenta in rats, resulting in blood levels in the fetus that approximately equal the blood level in the mother.8 Thus exposure by the dermal route was almost certainly high, and airborne exposures cannot be disregarded. In answer to our critic's disagreement with "the line of reasoning that links a single stillbirth with an exposure to NMP" we presented our article as a case report and literature review with all of the limitations thereof. Clearly it is premature to draw any definitive conclusions about the reproductive toxicity of NMP in humans on the basis of one case report. On the other hand, case reports can often provide important information for hypothesis generation and can sometimes provide an early warning system for human health effects that may become a problem in the future. Late-term stillbirths in mothers with no risk factors are blessedly rare events in clinical practice-far rarer than the overall incidence cited by the NMP producers. Although we cannot conclusively link the exposure to NMP with the stillbirth in this case, the situation was unusual enough from a clinical point of view, and strikingly similar enough to the findings reported from animal studies, that it is worthy of attention from the occupational and environmental medicine and research communities. Gina M Solomon, MD, MPH Natural Resources Defense Council San Francisco, CA Elise P. Morse, MPH Massachusetts Department of Public Health Boston, MA Maxine J. Garbo, MS Donald K. Milton, MD, DrPH Occupational Health Program Harvard School of Public Health Boston, MA
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Jun 1, 2004
Peter W Schuhmann + 1
Open Access