USTUR whole body case 0262: 33-y follow-up of PuO2 in a skin wound and associated axillary node.

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).

Ustur whole body case 0269: demonstrating effectiveness of i.v. CA-DTPA for Pu.

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.

Large granular lymphocytic (LGL) leukemia in rats exposed to intermittent 60 Hz magnetic fields.

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.

Effects of 50- or 60-hertz, 100 microT magnetic field exposure in the DMBA mammary cancer model in Sprague-Dawley rats: possible explanations for different results from two laboratories.

In line with the possible relationship between electric power and breast cancer risk and the underlying melatonin hypothesis, 50-Hz magnetic field (MF) exposure at microtesla flux densities for either 13 or 27 weeks significantly increased the development and growth of mammary tumors in a series of experiments from Löscher's group in Germany. Löscher's group used the 7,12-dimethylbenz[a]anthracene (DMBA) model of breast cancer in Sprague-Dawley rats. The finding could not be replicated when a similar experimental protocol was used in a study conducted by Battelle in the United States. In the present paper, investigators from the two groups discuss differences between their studies that might explain the apparent discrepancies between the results. These differences include the use of different substrains of Sprague-Dawley rats (the U.S. rats were more susceptible to DMBA than the European rats), different sources for diet and DMBA, differences in environmental conditions, and differences in MF exposure metrics. Furthermore, the effects of MF exposure reported by Löscher's group, albeit significant, were weak. We also discuss the general problem of replicating such weak effects.

In vivo MRI measurements of tumor growth induced by dichloroacetate: implications for mode of action.

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.

Effect of constant light on DMBA mammary tumorigenesis in rats.

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, dimethylben-zanthracene (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).

Two-generation reproduction study of lewisite in rats.

Lewisite, a potent toxic vesicant and chemical warfare agent, is used in a number of research laboratories, is stored in large quantities at depot sites throughout the USA and is occasionally transported to distant sites. Thus, the potential for environmental or occupational exposure exists where lewisite is present. A 42-week two-generation study was conducted to determine the reproductive consequences of lewisite in parental male and female rats and their offspring. Rats were administered lewisite in sesame oil (0, 0.10, 0.25 or 0.60 mg kg-1 day-1 for 5 days a week) via intragastic intubation before mating, during mating and after mating until the birth of their offspring. The dams continued to receive lewisite during lactation. At weaning, male and female offspring of each group were selected to continue the study, receiving lewisite during adolescence, mating and throughout gestation and lactation. Lewisite had no adverse effect on reproduction performance, fertility or reproductive organ weights of male or female rats through two consecutive generations. No adverse effects to offspring were attributed to lewisite exposure. Minor changes in growth were the only maternal effects observed. Lewisite exposure of parental rats caused no gross or microscopic lesion in testes, epididymis, prostate, seminal vesicles, ovaries, uterus or vagina. The no-observable-effect level (NOEL) for the reproductive effects of Lewisite would be > 0.60 mg kg-1 day-1.

Effect of 13 week magnetic field exposures on DMBA-initiated mammary gland carcinomas in female Sprague-Dawley rats.

Several studies suggest that exposure to 50 Hz magnetic fields may promote chemically induced breast cancer in rats. Groups of 100 female Sprague-Dawley rats were initiated with four weekly 5 mg gavage doses of 7,12-dimethylbenz[a]anthracene (DMBA) starting at 50 days of age. After the first weekly DMBA administration, exposure to ambient fields (sham exposed), 50 Hz magnetic fields at either 1 or 5 G field intensity or 60 Hz fields at 1 G for 18.5 h/day, 7 days/week was initiated. Exposure continued for 13 weeks. A vehicle control group without DMBA was included. In a second study, using lower doses of DMBA, groups of 100 female Sprague-Dawley rats were initiated with four weekly doses of 2 mg of DMBA starting at 50 days of age followed, after the first weekly DMBA administration, by exposure to ambient fields (sham exposed) or 50 Hz magnetic fields at either 1 or 5 G field intensity for 18.5 h/day, 7 days/week for 13 weeks. Rats were weighed and palpated weekly for the presence of tumors. There was no effect of magnetic field exposure on body weight gains or on the time of appearance of mammary tumors in either study. At the end of 13 weeks, the animals were killed and the mammary tumors counted and measured. Mammary gland masses found grossly were examined histologically. In the first 13 week study, the mammary gland carcinoma incidences were 92, 86, 96 and 96% for the DMBA controls, 1 G, 50 Hz, 5 G, 50 Hz and 1 G, 60 Hz groups, respectively. The total numbers of carcinomas were 691, 528 (P < 0. 05, decrease), 561 and 692 for the DMBA controls, 1 G, 50 Hz, 5 G, 50 Hz and 1 G, 60 Hz groups, respectively. In study 2, the mammary gland carcinoma incidences were 43, 48 and 38% for the DMBA controls, 1 G, 50 Hz and 5 G, 50 Hz groups, respectively. The total numbers of carcinomas were 102, 90 and 79 for the DMBA controls, 1 G, 50 Hz and 5 G, 50 Hz groups, respectively. There was no effect of magnetic field exposure on tumor size either by in-life palpation or by measurement at necropsy in either study. There was no evidence that 50 or 60 Hz magnetic fields promoted breast cancer in these studies in female rats. These studies do not support the hypothesis that magnetic field exposure promotes breast cancer in this DMBA rat model.

Effect of 26 week magnetic field exposures in a DMBA initiation-promotion mammary gland model in Sprague-Dawley rats.

Several studies have suggested that exposure to 50 Hz magnetic fields promote chemically induced breast cancer in rats. Groups of 100 female Sprague-Dawley rats were initiated with a single 10 mg gavage dose of 7,12-dimethylbenz[a]anthracene (DMBA) at 50 days of age followed by exposure to ambient fields (sham exposed), 50 Hz magnetic fields at either 1 or 5 Gauss (G) field intensity or 60 Hz fields at 1 G for 18.5 h/day, 7 days/week for 26 weeks. A vehicle control group without DMBA was included. Rats were palpated weekly for the presence of tumors. There was no effect of magnetic field exposure on body weight gains or the time of appearance of mammary tumors. At the end of 26 weeks, the animals were killed and the mammary tumors counted and measured. Mammary gland masses found grossly were examined histologically. The mammary gland carcinoma incidence was 96, 90, 95 and 85% (P < 0.05, decrease) for the DMBA controls, 1 G 50 Hz, 5 G 50 Hz and 1 G 60 Hz groups, respectively. The total numbers of carcinomas were 649, 494 (P < 0.05, decrease), 547 and 433 (P < 0.05, decrease) for the DMBA controls, 1 G 50 Hz, 5 G 50 Hz and 1 G 60 Hz groups, respectively. The number of fibroadenomas varied from 276 to 319, with the lowest number in the 1 G 60 Hz exposure group. Measurement of the tumors revealed no difference in tumor size between groups. In this breast cancer initiation-promotion study in female Sprague-Dawley rats, there was no evidence that 50 or 60 Hz magnetic fields promoted breast cancer under the conditions of this assay. This study does not support the hypothesis that magnetic field exposure can promote breast cancer in this rat model.

Effects of 60 Hz magnetic field exposure on the pineal and hypothalamic-pituitary-gonadal axis in the Siberian hamster (Phodopus sungorus).

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 microT 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.

Lack of effect of a 60 Hz magnetic field on biomarkers of tumor promotion in the skin of SENCAR mice.

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.

Clinical progression of transplanted large granular lymphocytic leukemia in Fischer 344 rats exposed to 60 Hz magnetic fields.

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 microT) fields], 3) ambient controls [<1 mG (0.1 [microT)], 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 x 10(7) 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.

Lack of a co-promoting effect of a 60 Hz magnetic field on skin tumorigenesis in SENCAR mice.

It has been proposed that extremely low frequency (ELF) 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 tumors in mice initiated by a single subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Experimentation described herein utilized the SENCAR mouse and examined the effect of a magnetic field on skin tumor promotion induced by three different doses of TPA within its dose-response range, i.e. 0.85, 1.70 or 3.40 nmol, administered twice per week. SENCAR mice (56/treatment group) were exposed to a 60 Hz magnetic field having a flux density of 2 mT for 6 h/day for 5 days/week and compared with mice exposed to the ambient magnetic field. Tumor incidence and multiplicity were monitored weekly for 23 weeks of TPA promotion. Statistical evaluation of the effects of the magnetic field on tumor incidence and multiplicity did not reveal any statistically significant effects; thus, within the sensitivity limits imposed by the animal model and the exposure parameters employed, no promotional or co-promotional effect of a 2 mT magnetic field on skin tumor development in SENCAR mice could be demonstrated.

Exposure to 60 Hz magnetic fields does not alter clinical progression of LGL leukemia in Fischer rats.

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.

Two-generation reproduction study of sulfur mustard in rats.

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.

Subchronic toxicity evaluation of lewisite in rats.

Health and exposure criteria have not been established for lewisite [dichloro(2-chlorovinyl)arsine], a potent toxic vesicant that reacts with the sulfhydryl groups of proteins through its arsenic group. Sixty Sprague-Dawley rats of each sex, 6-7 wk old, were divided into 6 groups (10/group/sex) and gavaged with either 0, 0.01, 0.1, 0.5, 1.0, or 2.0 mg/kg of lewisite in sesame oil 5 d/wk for 13 wk. No significant dose-related change in body weight was observed. At the high dose, serum protein, creatinine, SGOT, and SGPT were decreased in males; lymphocytes and platelets were increased in females. A treatment-related lesion was detected in the forestomach of both sexes at 2.0 mg/kg. These lesions were characterized by necrosis of the stratified squamous epithelium accompanied by infiltration of neutrophils and macrophages, proliferation of neocapillaries, hemorrhage, edema, and fibroblast proliferation. Mild acute inflammation of the glandular stomach was also observed in some cases at 1.0 and 2.0 mg/kg. Early deaths were attributed to severe inflammation of the upper and/or lower respiratory tract, possibly from deposition or reflux of test material into the pharynx. Estimated dose range for NOEL appears to be >0.5 and <1.0 mg/kg when administered orally.

Subchronic toxicity evaluation of sulfur mustard in rats.

Occupational exposure criteria have not been established for sulfur mustard (bis(2-chlorethyl) sulfide), a strong alkylating agent with known mutagenic properties. Seventy-two Sprague-Dawley rats of each sex, 6-7 weeks old, were divided into six groups (12 of each sex per group) and gavaged with 0, 0.003, 0.01, 0.03, 0.1 or 0.3 mg kg-1 sulfur mustard in sesame oil for 5 days a week for 13 weeks. No dose-related mortality was observed. A significant decrease (P > 0.05) in body weight was observed in both sexes of rats only in the 0.3 mg kg-1 group. Hematological evaluations and clinical chemistry measurements found non consistent treatment-related effects at the doses studied. The only treatment-related lesion associated with gavage exposure upon histopathological evaluation was epithelial hyperplasia of the forestomach of both sexes at 0.3 mg kg-1 and of males at 0.1 mg kg-1. The hyperplastic change was minimal and characterized by cellular disorganization of the basilar layer, apparent increase in mitotic activity of the basilar epithelial cells and thickening of the epithelial layer due to the apparent increase in cellularity. The estimated no-observed-effect level (NOEL) for sulfur mustard in this 90-day study was 0.1 mg kg-1 day-1 when administered orally.

Dominant lethal study of sulfur mustard in male and female rats.

Sulfur mustard (HD) (bis(2-chloroethyl)sulfide) is a strong alkylating agent with known mutagenic and suspected carcinogenic properties, but occupational health standards have not been established. The purpose of this study was to determine the dominant lethal effect in male and female rats dosed orally with HD, for which currently available data are ambiguous. Sprague-Dawley rats of each sex, 6-7 weeks old, were orally administered 0, 0.08, 0.20 or 0.50 mg kg-1 HD 5 days a week for 10 weeks, after which dominant lethal studies were conducted during the post-exposure period. The studies were conducted in two phases: a female dominant lethal phase in which treated or untreated males were mated with treated females and their fetuses were evaluated 14 days after copulation; and a male dominant lethal phase in which treated males cohabited with untreated females for 5 days and fetuses were evaluated 14 days after the mid-point of the week of cohabitation, for each of 10 weeks. In addition, motility, population size and morphology were measured in sperm obtained from the cauda epididymis. Parental growth rates were reduced in both sexes treated with the high level of HD. Female dominant lethal effects were not observed, although significant male dominant lethal effects were observed in HD-exposed male rats mated to untreated females at 2 and 3 weeks' post-exposure. These effects, which included increases of early fetal resorptions and preimplantation losses and decrease in total live embryo implants, were most consistently observed at a dose of 0.50 mg kg-1. A significant P(P < 0.05) increase in the percentage of abnormal sperm was detected in males exposed to 0.50 mg kg-1 HD. The timing of dominant lethal effects is consistent with an effect during the post-meiotic stages of spermatogenesis, possibly involving the generally sensitive spermatids.

Elevated blood pressure and heart rate in rats exposed to a coal-derived complex organic mixture.

The susceptibility of the cardiovascular system to exposure to a high-boiling coal liquid (heavy distillate, HD) was studied in the rat using an isoproterenol (ISO) myocardial infarction model. Male Fischer rats were exposed to HD by inhalation (0.7 mg/l), 6 h/day, 5 days/week, for 6 weeks. After a 10-day recovery period, sham-exposed and HD-exposed rats were injected subcutaneously with 0, 20, 40 or 60 mg ISO/kg body weight. Blood pressure, heart rate, electrocardiogram and 99mTc uptake by the heart were measured 1 day later. A dose-related increase was observed in the uptake of 99mTc by the hearts of both sham-exposed and HD-exposed animals after ISO injection; however, uptake by the sham-exposed group was significantly greater than that of exposed groups. The most striking observation was a 20% elevation in arterial blood pressure of HD-exposed rats over that of sham-exposed animals when no ISO was injected. These results suggest that the cardiovascular system could be detrimentally affected by exposure to coal-derived complex mixtures and, possibly, to other complex organic mixtures.

Cardiovascular effects in rats following exposure to a high-boiling coal liquid.

In previous work, increased blood pressure was observed in anesthetized rats following a subchronic aerosol exposure to solvent-refined coal heavy distillate (HD). To determine if this increase is a permanent, dose-related response, 11-week-old male rats were exposed by inhalation to 0, 0.24, or 0.70 mg/liter (control, low-exposure, and high-exposure groups, respectively) of HD for 6 hr/day, 5 days/week, for 6 weeks. In addition to blood pressure, select cardiovascular parameters were measured to obtain information on other possible toxic effects of the HD and also to gain some insight into potentially altered regulatory mechanisms that could be affecting the blood pressure. The angiotensin-aldosterone hormonal system, body fluid regulation, cardiac function and regulation, and pulmonary gas-exchange capabilities were examined. Two weeks after the end of exposure, mean blood pressures and heart rates of anesthetized animals in the low-and high-exposure groups were elevated relative to the controls. Plasma angiotensin concentrations decreased with increasing dose, whereas aldosterone concentrations were unaffected. In the high-dose group, blood and plasma volumes were 20 and 28%, respectively, higher than those of controls. Seven weeks after exposure, all measured cardiovascular parameters were similar to control values. Results from this study show that a 6-week exposure to HD resulted in dose-dependent, transient changes in a variety of physiological factors considered important in cardiovascular function.