Bone cancer from radium: canine dose response explains data for mice and humans.

Analysis of lifetime studies of 243 beagles with skeletal burdens of radium-226 shows that the distribution of bone cancers clusters about a linear function of the logarithms of radiation dose rate to the skeleton and time from exposure until death. Similar relations displaced by species-dependent response ratios also provide satisfactory descriptions of the reported data on deaths from primary bone cancers in people and mice exposed to radium-226. The median cumulative doses (or times) leading to death from bone tumors are 2.9 times larger for dogs than for mice and 3.6 times larger for people than for dogs. These response ratios are well correlated with the normal life expectancies. The cumulative radiation dose required to give significant risk of bone cancer is found to be much less at lower dose rates than at higher rates, but the time required for the tumors to be manifested is longer. At low dose rates, this time exceeds the normal life-span and appears as a practical threshold, which for bone cancer is estimated to occur at an average cumulative radiation dose to the skeleton of about 50 to 110 rads for the three species.

Squamous cell carcinoma in the jaws of beagles exposed to 90Sr throughout life: beta flux measurements at the mandible and tooth surfaces and a hypothesis for tumorigenesis.

We present the first detailed dose-response measurements for 90Sr-induced soft tissue tumors other than hemopoietic dyscrasias in chronically exposed beagles. Twenty-four of 387 dogs exposed to 90Sr beginning in utero and by continuous ingestion to 540 days of age developed squamous cell carcinoma of the jaw during their lifetime. Eleven of the 24 tumors were observed in dogs ingesting 12 microCi/day and receiving cumulative average doses of 6500-12,000 rad. None of these tumors was observed in dogs ingesting less than 1.25 microCi/day and receiving cumulative skeletal average doses of 2100-3900 rad, but four were observed at this level. The teeth of these animals acquired a 90Sr burden that is not removed by skeletal remodeling. Measurements of the radiation dose to soft tissue adjacent to the mandible and teeth of dogs chronically fed 90Sr indicated the first 10 micron of soft tissue adjacent to teeth received a radiation dose initially about the same as the average skeletal doses. By 2000-3000 days, these tissues received about two to three times that calculated for the average skeletal dose, or about four to six times the mean marrow dose. We suggest that these tumors arise from epithelial rests, which are embryonic tissue trapped in the periodontal membrane between teeth and bone.

The neurobiology of social phobia.

Studies in the neurobiology of social phobia have used neuroendocrine, naturalistic and chemical challenges, pharmacological probes, neurotransmitter system measures, peripheral receptor binding and magnetic resonance measures. Studies of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes have been largely unrevealing; adrenaline, carbon dioxide, caffeine and yohimbine tests have provided mixed results; probe studies using L-dopa, clonidine and fenfluramine have provided some evidence of post-synaptic serotonergic abnormality; studies on platelet and lymphocyte binding have failed to distinguish social phobia from other groups; magnetic resonance imaging and magnetic resonance spectroscopy studies suggest possible differences between patients with social phobia and healthy controls in respect of dopamine, serotonin and second-messenger function. In aggregate, these studies have provided some neurobiological basis for separating social phobia from panic disorder and non-psychiatric healthy controls.

Embryotoxicity and dose-response relationships of selenium in hamsters.

Pregnant hamsters were treated with selenite, selenate, and selenomethionine during the critical stages of embryogenesis. The dosing regimens were oral, intravenous, and osmotic minipump infusion. Malformations, mainly encephaloceles, were noted with oral and intravenous selenite and selenate but were associated with maternal toxicity manifested by inanition and weight loss. Fetal body weights and lengths were reduced in a dose-dependent manner with the inorganic forms. Single oral doses of selenomethionine above 77 mumol/kg induced similar malformations but not when the dose was delivered orally over four days nor by minipump over several days. Fetal body weights and lengths were decreased by selenomethionine in a dose-dependent manner. Maternal toxicity was pronounced with the higher doses of selenomethionine. Assigning a specific teratogenic effect to selenium is confounded by maternal toxicity.

Prioritizing candidate reproductive/developmental toxicants for evaluation.

To provide a rational method for the timely evaluation of possible reproductive/developmental toxicants, a prioritization scheme was developed by the California Department of Health Services to select chemicals for consideration by the Proposition 65 Scientific Advisory Panel. Initially, four ascertainment methods were used to identify and construct a master list of 164 candidate agents. Using two criteria, the potential for human exposure and the perceived reproductive/developmental hazard as judged by an ad hoc committee of experts, 42 candidates from the master list were identified as priority agents. For practical purposes, the 15 priority agents with the highest rankings will be given the highest priority in the review process. Limitations in the prioritization method used and refinements to be incorporated in an annual update are described.

Iodine-129 uptake and effects of lifetime feeding in rats.

Irradiation of thyroid glands in rats at a dose rate of approximately 1 rad/day from continually ingested 129I resulted in no significant increase in thyroid tumors compared to controls, nor in other thyroidal effects, nor was there any difference in longevity between the two groups. Marked decreases in 131I uptake by thyroid glands of 129I-fed rats were observed, but these decreases reflected "blocking" of the thyroid by the large quantities of iodine required because of the low specific activity of 129I. In view of the lack of effects on the thyroid gland invoked by lifetime exposures to 129I, and considering the low specific activity of the radionuclide and the limited capacity of the thyroid gland for iodine, the hazard from 129I appears to be extremely limited.

Lifetime bone cancer dose-response relationships in beagles and people from skeletal burdens of 226Ra and 90Sr.

The life-time tumor dose-response relationships observed in beagles injected with 226Ra or fed 90Sr at the University of California, Davis, provide a basis for understanding the induction of bone cancer for these bone-seeking radionuclides and for scaling to people. In these studies 385 dogs were exposed to graded dosage levels of 90Sr and 243 dogs were exposed to graded dosage levels of 226Ra with a total of 159 unexposed controls. The results show different dose-response relationships for bone cancer for the two radionuclides based upon the gravimetric average dose rates and cumulative doses to bone. These relationships were found to be well represented by three-dimensional log-normal dose-response surfaces that yield risk as a function of average dose-rate and time after beginning of exposure. All dose-rates suggested a 100% risk at some later time post-exposure but the time required to reach a given level of risk was long for low dose rates so that there exists a practical threshold in that at lower dose rates individuals may die spontaneously from causes associated with natural aging prior to the expected appearance of radiogenic cancer. The risks to people at various 226Ra body burdens (average skeletal dose rates) are estimated based on the model.