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mg/kg body wt resulted in pancreatic tumors in
50% and liver tumors in 100% of the hamsters; no
lung tumors were seen. When the BOP dose was
reduced by one-half, contrary to our expectations,
many lung tumors were induced in addition to a
few liver, renal and gall bladder neoplasms.
The increasing response of the SGH’s pancreas
to the neoplastic effect of BOP was demonstrated
by a single subcutaneous injection. Pancreatic
adenomas and adenocarcinomas developed in
nine out 15 hamsters of the high dose (40 mg/kg
b.w), six out of 15 in the next lower dose (20
mg/kg/b.w) and in one out of 15 in the low dose
group (5 mg/kg.b.w). Only a few tumors were
found in other target tissues but none in the low
dose group. Thus, the results indicated that
selective induction of pancreatic tumors in
hamsters was possible. This possibility was
verified by a subsequent experiment in which
hamsters were treated with a single low dose of
BOP (from 1/5 to 1/40 of the LD50). The incidence
of pancreatic tumors decreased by decreasing the
dose as did that of other target tissues; the lowest
effective dose was 5 mg/kg, which induced an
incidence of 15% in a females and 26% in males
and a few tumors in the liver in one (7%) female
and 0% in males, in gall bladder (in 2 males only),
and kidney (in one female only). The lowest dose
(2.5 mg/kg) did not produce any tumors 158 .
To further lower the incidence or to possibly
eliminate extra-pancreatic tumor induction, we
planned yet another experiment 159 with the
rationale that smaller doses given within a limited
time period could yield a desirable result. BOP
was given at a dose of 10 mg/kg body wt weekly
for six weeks. Two weeks later hamsters were
serially sacrificed at two-week intervals. No
tumors were found in hamsters sacrificed at eight
weeks; however, two weeks later, about 50% of
the animals developed pancreatic tumors. These
were the only induced neoplasms. During the
38
following weeks, the pancreatic tumor incidence
increased gradually and at 16 weeks all hamsters
had pancreatic tumors. Lung neoplasms
developed in 12% of hamsters at the end of 18
weeks. At this time, all the males were dead and
all females examined at a later time exhibited
pancreatic neoplasms and only a few lung,
kidney, and gall bladder tumors. Encouraged by
these findings, we initiated additional experiments
at various dose regimens and finally succeeded in
inducing pancreatic tumors selectively by single
BOP injections. In these experiments 158 , animals
without pancreatic neoplasms had no other
tumors, which could be attributed to the treatment.
In fact, more than 80% of treated hamsters had
pancreatic tumors only. Induction of pancreatic
tumors by a dose of 2.5 mg/kg body wt,
corresponding to 3/4 of the lethal toxic doses
(LD50) was striking and indicated a specific affinity
of this carcinogen for the pancreas 158
Although the results demonstrated the specific
reactivity of the hamster pancreas to BOP, the
search for other pancreatic carcinogens
continued. Among the postulated metabolites of
DPN by the β-oxidation theory of Krüger, Nnitroso2,6-dimethylmorpholine
(NDMM) was
tested by Mohr et al. in SGH. More than 70% of
hamsters developed pancreatic adenocarcinoma,
some with metastases into the lung 160 .
Assuming that the BOP and BHP are metabolized
by the β-oxidation to N-nitroso(2hydroxypropyl)(2-oxopropyl)amine
(HPOP)(Figs.
39,40), we tested its carcinogenicity in the SGH of
the Eppley colony. As with BOP, HPOP induced a
higher incidence of pancreatic cancer than BHP
and NDMM 161 . Also like BOP, HPOP induced
tumors in other tissues, including the liver, gall
bladder, kidneys and vagina. HPOP, unlike BOP,
induced tumors in the nasal cavity, larynx,
trachea, intestine, Harderian glands, lips and flank
organ.