Toxicological Sciences, Vol 50, 259-270, Copyright © 1999 by Society of Toxicology
E Weller, N Long, A Smith, P Williams, S Ravi, J Gill, R Henessey, W Skornik, J Brain, C Kimmel, G Kimmel, L Holmes and L Ryan
In risk assessment, evaluating a health effect at a duration of exposure
that is untested involves assuming that equivalent multiples of
concentration (C) and duration (T) of exposure have the same effect. The
limitations of this approach (attributed to F. Haber, Zur Geschichte des
Gaskrieges [On the history of gas warfare], in Funf Vortrage aus den Jahren
1920-1923 [Five lectures from the years 1920- 1923], 1924, Springer,
Berlin, pp. 76-92), have been noted in several studies. The study presented
in this paper was designed to specifically look at dose-rate (C x T)
effects, and it forms an ideal case study to implement statistical models
and to examine the statistical issues in risk assessment. Pregnant female
C57BL/6J mice were exposed, on gestational day 7, to ethylene oxide (EtO)
via inhalation for 1.5, 3, or 6 h at exposures that result in C x T
multiples of 2100 or 2700 ppm- h. EtO was selected because of its short
half-life, documented developmental toxicity, and relevance to exposures
that occur in occupational settings. Concurrent experiments were run with
animals exposed to air for similar periods. Statistical analysis using
models developed to assess dose-rate effects revealed significant effects
with respect to fetal death and resorptions, malformations, crown-to-rump
length, and fetal weight. Animals exposed to short, high exposures of EtO
on day 7 of gestation were found to have more adverse effects than animals
exposed to the same C x T multiple but at longer, lower exposures. The
implication for risk assessment is that applying Haber's Law could
potentially lead to an underestimation of risk at a shorter duration of
exposure and an overestimation of risk at a longer duration of exposure.
Further research, toxicological and statistical, are required to understand
the mechanism of the dose-rate effects, and how to incorporate the
mechanistic information into the risk assessment decision process.
ARTICLES
Dose-rate effects of ethylene oxide exposure on developmental toxicity
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
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