Three retinoids of the arotinoid series, namely the free carboxylic acid Ro 13-7410, its ethyl ester Ro 13-6298, and the new arotinoid ethyl sulfone Ro 15-1570, were tested for their embryotoxic and teratogenic activity in rats. The retinoids were administered orally on either day 9 or 13 of gestation. Treatment on day 9 of gestation resulted mainly in malformations of the head and the trunk; whereas, on day 13 limb malformations were prominent. Ro 13-7410 and Ro 13-6298 were about 1000 times more embryotoxic and teratogenic than retinoic acid but induced a similar malformation pattern to retinoic acid. In contrast, the sulfur-containing arotinoid Ro 15-1570 was active at similar dose levels to retinoic acid but caused a peculiar malformation pattern on day 13 of gestation. This finding supports the hypothesis that the arotinoid ethyl sulfone Ro 15-1570 has unique biological properties, inducing no bone toxicity in adult rats and distinctly affecting limb development.

Pregnant hamsters were given a single oral dose (35 mumol/kg) of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, 9-cis-retinal or all-trans-retinyl acetate during the early primitive streak stage of development. The radioactivity associated with the acidic retinoids was distributed to all tissues sampled (including placenta and fetus), with the largest accumulation in the liver and the least accumulation in fat. Radioactivity from 9-cis-retinal or retinyl acetate concentrated in the liver and lung. The all-trans-retinoic acid was oxidized in vivo to all-trans-4-oxo-retinoic acid and isomerized to 13-cis-retinoic acid: 13-cis-retinoic acid was oxidized to 13-cis-4-oxo-retinoic acid and isomerized to all-trans-retinoic acid. No parent 9-cis-retinal or retinyl acetate could be detected in maternal plasma. Plasma concentrations of the parent acidic retinoids reached their maxima within 60 min and then followed exponential decay. Of all the retinoids examined here, 13-cis-retinoic acid showed the largest area under the plasma curve, the slowest clearance and the longest elimination t1/2. Total plasma radioactivity, consisting of unidentified metabolites, remained elevated at 4 days after dosing. Maternal peak circulating concentrations of the parent retinoids, total radioactivity, plasma pharmacokinetic parameters or the total concentrations of residual radioactivity in fetal tissues could not be correlated with the differential teratogenic potencies of these retinoids.

Preparations are ongoing to test the viability and usefulness of an accelerator source of epithermal neutrons for ultimate use in a clinical environment. This feasibility study is to be conducted in a shielded room located on the Massachusetts Institute of Technology campus and will not involve patient irradiations. The accelerator production of neutrons is based on the 7Li(p, n)7Be reaction, and a maximum proton beam current of 4 mA at an energy of 2.5 MeV is anticipated. The resultant 3.58 x 10(12) neutrons s-1 have a maximum energy of 800 keV and will be substantially moderated. This paper describes the Monte Carlo methods used to estimate the neutron and photon dose rates in a variety of locations in the vicinity of the accelerator, as well as the shielding configuration required when the device is run at maximum current. Results indicate that the highest absorbed dose rate to which any individual will be exposed is 3 microSv h-1 (0.3 mrem h-1). The highest possible yearly dose is 0.2 microSv (2 x 10(-2) mrem) to the general public or 0.9 mSv (90 mrem) to a radiation worker in close proximity to the accelerator facility. The shielding necessary to achieve these dose levels is also discussed.