Methyl iodide (MeI) is a water soluble monohalomethane that is metabolized in vivo to release iodide (I−). A physiologically based pharmacokinetic (PBPK) model exists for iodide in adult rats, pregnant rats and fetuses, and lactating rats and neonates, but not for pregnant rabbits and fetuses, which have been used extensively for toxicity testing with MeI. Thus, this study was conducted to determine the blood and tissue distribution kinetics of radioiodide in pregnant rabbits and fetuses. Timed-pregnant New Zealand White rabbits received a single intravenous injection of the sodium salt of iodine-131 (Na131I) at either a high (10 mg/kg body weight) or low (0.75 mg/kg body weight) dose on gestation day 25. At various intervals ranging from 0.5 to 24 h post- injection, blood and tissues (thyroid, stomach contents, and skin) were collected from each doe, and blood, stomach contents, thyroid, trachea, and amniotic fluid were collected from a random sampling of three fetuses per doe per time point. Radioiodide accumulated as expected in the thyroid of maternal animals, where concentrations were the highest of any maternal tissues measured in both dose groups. Radioiodide also accumulated in fetal blood and tissues; levels were consistently higher than maternal levels and, unlike maternal tissues, showed no evidence of clearance over the 24-h sampling period. In contrast to observations in the maternal animals, fetal stomach contents showed the highest accumulation of radioiodide for both dose groups by 1–2 h after dosing, followed by the trachea and thyroid tissues, with the lowest concentrations of radioiodide in the amniotic fluid and blood. There was no evidence for preferential accumulation of radioiodide in fetal thyroid tissues.

EFFECTIVENESS OF I.V. CA-DTPA FOR PU A. C. James1,*, L. B. Sasser1, D. B. Stuit1, S. E. Glover2 and E. H. Carbaugh3 US Transuranium and Uranium Registries, College of Pharmacy, Washington State University, 1845 Terminal Drive, Suite 201, Richland, WA 99354, USA Department of Mechanical, Industrial and Nuclear Engineering, University of Cincinnati, 598 Rhodes Hall, Cincinnati, OH 45221, USA Pacific Northwest National Laboratory, PO Box 999, Richland, WA 99354, USA

This whole body donation case (USTUR Registrant) involved two suspected PuO2 inhalation intakes, each indicated by a measurable Pu alpha activity in a single urine sample, followed about 1(1/2) y later by a puncture wound to the thumb while working in a Pu glovebox. The study is concerned with modelling simultaneously the biokinetics of deposition and retention in the respiratory tract and at the wound site; and the biokinetics of Pu subsequently transferred to other body organs, until the donor's death. Urine samples taken after the wound incident had readily measurable Pu alpha activity over the next 14 y, before dropping below the minimum detectable excretion rate (<0.4 mBq d(-1)). The Registrant died about 33 y after the wound intake, at the age of 71, from hepatocellular carcinoma with extensive metastases. At autopsy, all major soft tissue organs were harvested for analysis of their 238Pu, 239+240Pu and 241Am content. The amount of 239+240Pu retained at the wound site was 68 +/- 7 Bq (1 SD), measured by low-energy planar Ge spectrometry. A further 56.0 +/- 1.2 Bq was retained in an associated axillary lymph node, measured by radiochemistry. Simultaneous mathematical analysis (modelling) of all in vivo urinary excretion data, together with the measured lung, thoracic lymph node, wound, axillary lymph node and systemic tissue contents at death, yielded estimated intake amounts of 757 and 1504 Bq, respectively, for the first and second inhalation incidents, and 204 Bq for the total wound intake. The inhaled Pu material was highly insoluble, with an estimated long-term absorption rate from the lungs of 2 x 10(-5) d(-1). The Pu material deposited at the wound site was mixed: approximately 14% was rapidly absorbed, approximately 49% was absorbed at the rate of about 6 x 10(-5) d(-1), and the remainder ( approximately 37%) was absorbed extremely slowly (at the rate of about 5 x 10(-6) d(-1)). Thus, it was estimated that only approximately 40% of the Pu initially deposited in the wound had been absorbed systemically over the 33-y period until the donor's death. The biokinetic modelling also indicated that, in this individual case, some of the parameter values (rate constants) incorporated in the ICRP Publication 67 Pu model were up to a factor of 2 different from ICRP's recommended values (for reference man).

This whole body donation case (USTUR Registrant) involved a single acute inhalation of an acidic Pu(NO3)4 solution in the form of an aerosol 'mist'. Chelation treatment with intravenously (i.v.) Ca-EDTA was initiated on the day of the intake, and continued intermittently over 6 months. After 2.5 y with no further treatment, a course of i.v. Ca-DTPA was administered. A total of 400 measurements of 239+240Pu excreted in urine were recorded; starting on the first day (both before and during the initial Ca-EDTA chelation) and continuing for 37 y. This sampling included all intervals of chelation. In addition, 91 measurements of 239+240Pu-in-feces were recorded over this whole period. The Registrant died about 38 y after the intake, at age 79 y, with extensive carcinomatosis secondary to adenocarcinoma of the prostate gland. At autopsy, all major soft tissue organs were harvested for radiochemical analyses of their 238Pu, 239+240Pu and 241Am content. Also, all types of bone (comprising about half the skeleton) were harvested for radiochemical analyses, as well as samples of skin, subcutaneous fat and muscle. This comprehensive data set has been applied to derive 'chelation-enhanced' transfer rates in the ICRP Publication 67 plutonium biokinetic model, representing the behaviour of blood-borne and tissue-incorporated plutonium during intervals of therapy. The resulting model of the separate effects of i.v. Ca-EDTA and Ca-DTPA chelation shows that the therapy administered in this case succeeded in reducing substantially the long-term burden of plutonium in all body organs, except for the lungs. The calculated reductions in organ content at the time of death are approximately 40% for the liver, 60% for other soft tissues (muscle, skin, glands, etc.), 50% for the kidneys and 50% for the skeleton. Essentially, all of the substantial reduction in skeletal burden occurred in trabecular bone. This modelling exercise demonstrated that 3-y-delayed Ca-DTPA therapy was as effective as promptly administered Ca-EDTA.

Abstract Anderson, L. E., Sheen, D. M., Wilson, B. W., Grumbein, S. L., Creim, J. A. and Sasser, L. B. Two-Year Chronic Bioassay Study of Rats Exposed to a 1.6 GHz Radiofrequency Signal. Radiat. Res. 162, 201–210 (2004). The purpose of this study was to determine whether long-term exposure to a 1.6 GHz radiofrequency (RF) field would affect the incidence of cancer in Fischer 344 rats. Thirty-six timed-pregnant rats were randomly assigned to each of three treatment groups: two groups exposed to a far-field RF Iridium signal and a third group that was sham exposed. Exposures were chosen such that the brain SAR in the fetuses was 0.16 W/kg. Whole-body far-field exposures were initiated at 19 days of gestation and continued at 2 h/day, 7 days/week for dams and pups after parturition until weaning (∼23 days old). The offspring (700) of these dams were selected, 90 males and 90 females for each near-field treatment group, with SAR levels in the brain calculated to be as follows: (1) 1.6 W/kg, (2) 0.16 W/kg and (3) near-field sham controls, with an additional 80 males and 80 females as shelf controls. Confining, head-first, near-field exposures of 2 h/day, 5 days/week were initiated when the offspring were 36 ± 1 days old and continued until the rats were 2 years old. No statistically significant differences were observed among treatment groups for number of live pups/litter, survival index, and weaning weights, nor were there differences in clinical signs or neoplastic lesions among the treatment groups. The percentages of animals surviving at the end of the near-field exposure were not different among the male groups. In females a significant decrease in survival time was observed for the cage control group.

This year was my fourteenth year with the U. S. Transuranium and Uranium Registries (USTUR). How time flies! Since I became the director of the program five years ago, one of my primary goals was to increase the usefulness of the large USTUR database that consists of six tables containing personal information, medical histories, radiation exposure histories, causes of death, and the results of radiochemical analysis of organ samples collected at autopsy. It is essential that a query of one or more of these tables by USTUR researchers or by collaborating researchers provides complete and reliable information. Also, some of the tables (those without personal identifiers) are destined to appear on the USTUR website for the use of the scientific community. I am pleased to report that most of the data in the database have now been verified and formatted for easy query. It is important to note that no data were discarded; copies of the original tables were retained and the original paper documents are still available for further verification of values as needed.

Abstract Vijayalaxmi, Sasser, L. B., Morris, J. E., Wilson, B. W. and Anderson, L. E. Genotoxic Potential of 1.6 GHz Wireless Communication Signal: In Vivo Two-Year Bioassay. Radiat. Res. 159, 558–564 (2003). Timed-pregnant Fischer 344 rats (from nineteenth day of gestation) and their nursing offspring (until weaning) were exposed to a far-field 1.6 GHz Iridium wireless communication signal for 2 h/day, 7 days/week. Far-field whole-body exposures were conducted with a field intensity of 0.43 mW/cm2 and whole-body average specific absorption rate (SAR) of 0.036 to 0.077 W/kg (0.10 to 0.22 W/kg in the brain). This was followed by chronic, head-only exposures of male and female offspring to a near-field 1.6 GHz signal for 2 h/day, 5 days/week, over 2 years. Near-field exposures were conducted at an SAR of 0.16 or 1.6 W/kg in the brain. Concurrent sham-exposed and cage control rats were also included in the study. At the end of 2 years, all rats were necropsied. Bone marrow smears were examined for the extent of genotoxicity, assessed from the presence of micronuclei in polychromatic erythrocytes. The results indicated that the incidence of micronuclei/2000 polychromatic erythrocytes were not significantly different between 1.6 GHz-exposed, sham-exposed and cage control rats. The group mean frequencies were 5.6 ± 1.8 (130 rats exposed to 1.6 GHz at 0.16 W/kg SAR), 5.4 ± 1.5 (135 rats exposed to 1.6 GHz at 1.6 W/kg SAR), 5.6 ± 1.7 (119 sham-exposed rats), and 5.8 ± 1.8 (100 cage control rats). In contrast, positive control rats treated with mitomycin C exhibited significantly elevated incidence of micronuclei/2000 polychromatic erythrocytes in bone marrow cells; the mean frequency was 38.2 ± 7.0 (five rats). Thus there was no evidence for excess genotoxicity in rats that were chronically exposed to 1.6 GHz compared to sham-exposed and cage controls.

Determining the key events in the induction of liver cancer in mice by trichloroethylene (TRI) is important in the determination of how risks from this chemical should be treated at low doses. At least two metabolites can contribute to liver cancer in mice, dichloroacetate (DCA) and trichloroacetate (TCA). TCA is produced from metabolism of TRI at systemic concentrations that can clearly contribute to this response. As a peroxisome proliferator and a species-specific carcinogen, TCA may not be important in the induction of liver cancer in humans at the low doses of TRI encountered in the environment. Because DCA is metabolized much more rapidly than TCA, it has not been possible to directly determine whether it is produced at carcinogenic levels. Unlike TCA, DCA is active as a carcinogen in both mice and rats. Its low-dose effects are not associated with peroxisome proliferation. The present study examines whether biomarkers for DCA and TCA can be used to determine if the liver tumor response to TRI seen in mice is completely attributable to TCA or if other metabolites, such as DCA, are involved. Previous work had shown that DCA produces tumors in mice that display a diffuse immunoreactivity to a c-Jun antibody (Santa Cruz Biotechnology, SC-45), whereas TCA-induced tumors do not stain with this antibody. In the present study, we compared the c-Jun phenotype of tumors induced by DCA or TCA alone to those induced when they are given together in various combinations and to those induced by TRI given in an aqueous vehicle. When given in various combinations, DCA and TCA produced a few tumors that were c-Jun+, many that were c-Jun-, but a number with a mixed phenotype that increased with the relative dose of DCA. Sixteen TRI-induced tumors were c-Jun+, 13 were c-Jun-, and 9 had a mixed phenotype. Mutations of the H-ras protooncogene were also examined in DCA-, TCA-, and TRI-induced tumors. The mutation frequency detected in tumors induced by TCA was significantly different from that observed in TRI-induced tumors (0.44 vs 0.21, p < 0.05), whereas that observed in DCA-induced tumors (0.33) was intermediate between values obtained with TCA and TRI, but not significantly different from TRI. No significant differences were found in the mutation spectra of tumors produced by the three compounds. The presence of mutations in H-ras codon 61 appeared to be a late event, but ras-dependent signaling pathways were activated in all tumors. These data are not consistent with the hypothesis that all liver tumors induced by TRI were produced by TCA.

An animal model for large granular lymphocytic (LGL) leukemia in male Fischer 344 rats was utilized to determine whether magnetic field exposure can be shown to influence the progression of leukemia. We previously reported that exposure to continuous 60 Hz, 1 mT magnetic fields did not significantly alter the clinical progression of LGL leukemia in young male rats following injection of spleen cells from donor leukemic rats. Results presented here extend those studies with the following objectives: (a) to replicate the previous study of continuous 60 Hz magnetic field exposures, but using fewer LGL cells in the inoculum, and (b) to determine if intermittent 60 Hz magnetic fields can alter the clinical progression of leukemia. Rats were randomly assigned to four treatment groups (18/group) as follows: (1) 1 mT (10 G) continuous field, (2) 1 mT intermittent field (off/on at 3 min intervals), (3) ambient controls ( < 0.1 microT), and (4) positive control (5 Gy whole body irradiation from cobalt-60 four days prior to initiation of exposure). All rats were injected intraperitoneally with 2.2 x 10(6) fresh, viable LGL leukemic spleen cells at the beginning of the study. The fields were activated for 20 h per day, 7 days per week, and all exposure conditions were superimposed over the natural ambient magnetic field. The rats were weighed and palpated for splenomegaly weekly. Splenomegaly developed 9-11 weeks after transplantation of the leukemia cells. Hematological evaluations were performed at 6, 8, 10, 12, 14, and 16 weeks of exposure. Peripheral blood hemoglobin concentration, red blood cells, and packed cell volume declined, and total white blood cells and LGL cells increased dramatically in all treatment groups after onset of leukemia. Although the positive control group showed different body weight curves and developed signs of leukemia earlier than other groups, differences were not detected between exposure groups and ambient controls. Furthermore, there were no overall effects of magnetic fields on splenomegaly or survival in exposed animals. In addition, no significant and/or consistent differences were detected in hematological parameters between the magnetic field exposed and the ambient control groups.

A study of light, and mammary tumorigenesis was conducted in rats. One-hundred female Sprague–Dawley rats were divided by weight into two groups. One group was exposed to constant light (LL) from 26 days of age, and the second group was exposed to 8 h light and 16 h dark per day (LD). Both groups received an 8 mg dose of a chemical carcinogen, dimethylbenzanthracene (DMBA) at 52 days of age. At 13 weeks post-DMBA, there were significantly fewer mammary tumors in the LL group compared with the LD group. Constant light was clearly demonstrated to have a profound effect on mammary tissue development. Although virgin, the majority of the LL rats (29/50) had gross evidence of lactation at 141 days of age. None of the LD rats (0/50) showed evidence of milk production. These results suggest that constant light not only substantially accelerated mammary gland development, but pushed development of the tissue past the stage normally observed in virgin animals (to the lactation stage).

The ability of trichloroethylene (TCE) to induce liver tumors in B6C3F1 mice has underpinned the development of environmental standards for the past two decades. Alternatives to linear extrapolation require demonstration that a mode of action is involved that is unlikely to have a linear dose-response relationship. Our laboratory approached this problem along two distinct paths. The first path involved the investigation of the formation and further metabolism of the metabolites postulated responsible for the induction of liver cancer by TCE, dichloroacetate (DCA) and trichloroacetate (TCA). The second path was to determine if modes of action could be demonstrated that would not require linear extrapolation for purposes of risk assessment. Sufficient TCA is produced in the metabolism of TCE to account for a substantial fraction of the liver tumors. DCA is also produced at very low concentrations in blood, but it is much active at much lower concentrations in vivo than TCA. It appears that DCA could account for the remaining tumors. TCA acts as a peroxisome proliferator. It has been argued that this class of carcinogens is not active in humans based on several grounds, the most persuasive being that its effects are mediated through the peroxisome proliferator activated receptor (PPAR) because the response can be blocked by disrupting the receptor with knockout mice. We found that that while DCA induces peroxisome proliferation, this does not appear to be its primary mode of action. The tumors produced by DCA are distinct from those produced by TCA. We have shown that DCA appeared to stimulate the growth of spontaneously initiated liver cells from mice on soft agar, suggesting that its weak mutagenic activity is not requirement for its tumorigenic effects. These results were confirmed in vivo by showing that the primary mode of action of DCA was to stimulate the rate of tumor growth utilizing magnetic resonance imaging. This was very consistent with our data showing that DCA had a selective ability to induce cell replication within preneoplastic lesions while depressing replication in normal cells. Modeling of these results suggest that tumor initiation by DCA is produced by suppression of apoptosis in a spontaneously mutated cells and fixation of these cells by stimulation of cell division. These results strongly suggest that DCA or TCA does not involve linear mechanisms in the induction of liver cancer. Since the tumors can be entirely accounted for by these two metabolites, induction of liver tumors by TCE does not require low-dose linear extrapolation. (Supported by the Environmental Management Science Program Contract No. RL3-7-SP-22 (Task 09))

Dichloroacetate (DCA) is an important by-product of the chlorination of drinking water that produces liver cancer in rodents. Assessment of the risk that results from concentrations that occur in drinking water will be dependent upon the mode of action held responsible for these tumors. A study by Stauber and Bull [Stauber, A.J. and Bull, R. J (1997) Differences in phenotype and cell replicative behavior of hepatic tumors inducted by dichloroacetate (DCA) and trichloroacetate (TCA). Toxicol. Appl. Pharmacol. 144, 235-246] in mice treated with DCA demonstrated a lesion distribution that was skewed towards many small, altered foci of cells that are assumed to be precursor lesions [EPA, (1996). U.S. Environmental Protection Agency: Proposed Guidelines for carcinogen risk assessment; notice. Fed. Reg. 61, pp. 17960-10811]. The present study was designed to determine the extent to which the tumorigenic effects of DCA could be explained by its effect on tumor growth rates (i.e. tumor promoting activity). In vivo magnetic resonance imaging (MRI) allowed accurate determination of growth rates of individual lesions in mice that had been treated with DCA in drinking water at 2 g/l. Out of thirty treated mice, ten were found to have hepatic tumors detectable by MRI at 48 weeks of treatment. These tumor-bearing animals were assigned to two groups matched on the size of lesions observed by in vivo MR1. Treatment with DCA continued in one group of five mice and was stopped in the other. For both groups, tumor growth rates were determined by measuring changes in size of all lesions greater than 1 mm(3) in volume during a 14-day period. Removal of DCA treatment resulted in growth rates that could not be distinguished from zero across all lesion sizes represented in the sample. These data are in agreement with previous observations of DCAs effects on replication rates within tumors (Stauber and Bull, (1997)). Tumor growth rates observed in animals maintained on treatment decreased with lesion volume in a manner that is consistent with a stochastic Gompertz birth-death process proposed by Tan [Tan, W.Y. (1986) A stochastic Gompertz birth-death process. Stat. Prob. Lett. 4, 25-28]. Parameters of this model obtained by fitting measured growth rates were used to predict the lesion-size distribution expected after one year of DCA treatment. The shape of the predicted lesion-size distribution was similar to that observed by Stauber and Bull (Stauber and Bull, (1997)) in mice sacrificed after 40 weeks of DCA treatment. We conclude that the effects of DCA on the division and/or death rates of spontaneously initiated cells can account for the predominance of small lesions in DCA-treated animals.

The purpose of this study was to determine if 60 Hz magnetic fields can alter the clinical progression of leukemia in an animal model. Large granular lymphocytic (LGL) leukemia cells from spleens of leukemic rats were transplanted into young male Fischer 344 rats, producing signs of leukemia in approximately 2–3 months. The animals were randomly assigned to 4 treatment groups (108/group) as follows: 1) 10 G (1.0 mT) linearly polarized 60 Hz magnetic fields, 2) sham exposed [null energized unit with residual 20 mG (2 μT) fields], 3) ambient controls [<1 mG (0.1 μT)], and 4) positive controls (a single 5 Gy whole body exposure to 60Co 4 days prior to initiation of exposure). All rats were injected intraperitoneally (ip) with 2.2 × 107 LGL leukemic cells at the initiation of exposure or sham exposure. The magnetic fields were activated for 20 h/day, 7 days/week, allowing time for animal care. The experimental fields were in addition to natural ambient magnetic fields. Eighteen rats from each treatment group were bled, killed, and evaluated at 5, 6, 7, 8, 9, and 11 weeks of exposure. Peripheral blood hematological endpoints, changes in spleen growth, and LGL cell infiltration into the spleen and liver were measured to evaluate the leukemia progression. No significant or consistent differences were detected between the magnetic field exposed groups and the ambient control group, although the clinical progress of leukemia was enhanced in the positive control animals. These data indicate that exposure to sinusoidal, linearly polarized 60 Hz, 10 G magnetic fields did not significantly alter the clinical progression of LGL leukemia. Furthermore, the data are in general agreement with previous results of a companion repeated-bleeding study in which animals were exposed for 18 weeks. Bioelectromagnetics 20:48–56, 1999. © 1999 Wiley-Liss, Inc.

It has been proposed that extremely low frequency magnetic fields may enhance tumorigenesis through a co-promotional mechanism. This hypothesis has been further tested using the two-stage model of mouse skin carcinogenesis, i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced promotion of skin carcinogenesis in mice initiated by a single subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Experimentation utilized three different doses of TPA within its dose-response range (0.85, 1.70 or 3.40 nmol) and examined the following early biomarkers of tumor promotion after 1, 2 and 5 weeks of promotion: increases in epidermal thickness and the labeling index of epidermal cells, induction of epidermal ornithine decarboxylase activity and down-regulation of epidermal protein kinase C activity, Mice exposed to a 60 Hz magnetic field having a flux density of 2 mT for 6 h/day for 5 days/week were compared with mice exposed to an ambient magnetic field. Within the sensitivity limits of the biomarker methodology and the exposure parameters employed, no consistent, statistically significant effects indicative of promotion or co-promotion by the magnetic field were demonstrated.

Experiments using the dwarf Siberian hamster Phodopus sungorus were carried out to determine possible neuroendocrine consequences of one-time and repeated exposures to 60 Hz magnetic fields (MF). Animals were maintained in either a short-light (SL, 8 h light:16 h dark) or long-light (LL, 16 h light:8 h dark) photoperiod. Acute (one-time, 15 min) exposure of male SL animals to a linearly polarized, horizontally oriented, 60 Hz MF (0.1 mT) gave rise to a statistically significant (P < .005) reduction in pineal melatonin content as determined 3 and 5 h after onset of darkness. In LL animals, acute exposure to 0.10 mT resulted in a significant decrease in pineal melatonin as measured 4 h after onset of darkness, whereas acute exposure to 50 μT showed no effect compared with sham exposure. In SL animals, an increase in norepinephrine was observed in the medial basal hypothalamus (including the suprachiasmatic nucleus) after acute exposure (P < .01). Daily MF exposure of SL animals to a combination of steady-state and on/off 60 Hz magnetic fields (intermittent exposure) at 0.1 mT for 1 h per day for 16 days was associated with a reduction in melatonin concentrations at 4 h after onset of darkness and an increase in blood prolactin concentrations (P < .05). Exposure of SL animals to a steady state 60 Hz MF for 3 h/day for 42 days resulted in a statistically significant reduction in body weight (ANOVA: P > .05), compared with sham-exposed SL animals. At 42 days, however, no significant changes in overnight melatonin or prolactin levels were detected. In both repeated exposure experiments, gonadal weights were lowest in the MF-exposed groups. This difference was statistically significant (P < .05) after 42 days of exposure. These data indicate that both one-time and repeated exposure to a 0.1 mT, 60 Hz MF can give rise to neuroendocrine responses in Phodopus. Bioelectromagnetics 20:224–232, 1999. © 1999 Wiley-Liss, Inc.

Comprehensive data are not available to evaluate the potential risk to reproduction from exposure to sulfur mustard (HD), [bis(2-chloroethyl) sulfide]; thus, the reproductive effects of HD were evaluated in Sprague-Dawley rats. Groups, of rats (27 females and 20 males/group/generation) were gavaged with 0, 0.03, 0.1, or 0.4 mg/kg HD 5 d/week for 13 weeks prior to mating and throughout gestation, parturition, and lactation in a 42-week, 2-generation study. Growth of adult F1 rats of both sexes was reduced by the 0.4 mg/kg exposure. There were no significant effects on reproductive function or pregnancy outcome in either generation, except for an altered sex ratio in the 0.4 mg/kg group. Although not different at birth, growth of the 0.4 mg/kg F1 and F2 offspring was depressed during lactation. A dose-related lesion of the squamous epithelium of the forestomach was observed in adults of both sexes and both the F1 and F2 generation. For a given treatment, the incidence was approximately the same for each sex at each generation. When animals were pooled by sex and generation, approximately 70% (66 out of 94) of the low dose group had only mild microscopic lesions, 72% (68 out of 94) of the intermediate dose group had moderate lesions, and 81 % (76 out of 94) of the high group had marked lesions. The lesion, acanthosis, was characterized by thickening of the squamous musoca with varying degrees of hyperkeratosis. Benign neoplasms of the forestomach were found in about 10% of the intermediate and high dose groups in both F0 and F1 generations. Based on these results, the No-Observable-Adverse-Effect-Level (NOAEL) is 0.1 mg/kg/d.

Associations between exposure to 60-Hz magnetic fields in residential and occupational environments and the incidence of leukemia and other cancers has been suggested by the results of a number of epidemiology studies. To address these potential associations, a study has been conducted to determine if 60-Hz magnetic fields can alter the clinical progression of leukemia. In the large granular lymphocytic (LGL) leukemia model, spleen cells from aged leukemic rats were transplanted into young, male Fischer 344 rats, producing leukemia in a relatively short period. A total of 72 animals were randomly assigned to four treatment groups (18/group) as follows: (1) 10 G; (2) sham exposed (null energized field) (approximately 20 mG); (3) ambient controls (<1 mG); and (4) positive controls (5 Gy whole body irradiation from Cobalt-60, 4 days before initiation of exposure). At the initiation of exposure or sham-exposure, all rats were injected (i.p.) with 2.2x10(7) fresh, viable, LGL leukemia cells. The magnetic fields were activated for 20 h per day, 7 days per week; all exposure conditions were superimposed over the natural ambient magnetic field. Eighteen rats from each treatment were bled at weeks 0, 2, 4, 5, 6, 7, 8 and 10 to monitor, in the same set of animals, the clinical progression of the LGL disease and survival of the animals. Peripheral blood hematological changes were monitored to evaluate the progression of the leukemia. In general, no significant or consistent differences were detected between the magnetic field exposed and the ambient field control groups, although some inconsistent and random differences were occasionally observed. These data indicate that the 10 G magnetic fields did not significantly alter the clinical progression of LGL leukemia in Fischer 344 rats.