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hepatomas. The number of tumors at any site and the number of lung tumors in animals administered HN2 were significantly greater than expected at the 95 percent confidence level. Boyland and Horning noted a particular excess of lung tumors and lymphosarcomas compared to the number expected.

Heston's Studies in Mice

From 1949 through 1953, W. E. Heston and his colleagues conducted a series of studies in which sulfur mustard and nitrogen mustard were administered to strain A mice and the occurrence of pulmonary tumors was studied (Heston, 1949, 1950, 1953a,b; Heston et al., 1953). Strain A mice are highly inbred and have an extremely high genetic susceptibility for development of pulmonary adenomas; the incidence of spontaneous pulmonary tumors is about 50 percent in animals 12 months of age and 90 percent at 18 months of age. Thus, in several of Heston's experiments all of the animals developed adenomas, and comparisons can be made only between the total number of tumor nodules found in different exposure groups. The administered amounts of nitrogen and sulfur mustards were highly toxic, and a significant number of early deaths of animals occurred.

The results of the first two studies (Heston, 1949, 1950) are summarized in Table 6-1. In Experiment I, 100 percent of the experimental animals that survived acute mortality had tumors at sacrifice (13 to 16 weeks), compared to 13 percent of controls (the remaining 8 experimental and 8 control mice were followed longer, but no data were provided on their outcome). The mean number of lung nodules in the experimental group was 3.48, compared with 0.13 in the control group. The 9 animals receiving 4 injections had 5.11 nodules on average, the 13 receiving 3 injections had 2.62 nodules, and the lone animal with 2 injections had 2 nodules. The administered doses of nitrogen mustard clearly increased the number of nodules and number of strain A mice affected.

In Experiment II, all experimental animals received four injections and follow-up was continued for 10 months, rather than 3 or 4. The full dosing scheme led to several animals dying prior to completion of the experiment, but the results are in agreement with those of Experiment I, with a greater number of nodules being associated with the longer follow-up period. In Experiment III, a single larger injection of HN2 resulted in higher short-term mortality, but the incidence of tumor nodules in animals that survived 10 months was similar to the group that received the full dose in four injections.

Experiments IV and V followed a similar methodology to examine the effects of intravenous injection of sulfur mustard. Experiment IV saw a



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