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A high-boiling (288-454 degrees C), coal-derived complex organic mixture (COM) has been shown to be teratogenic in rats following inhalation and oral routes of exposure. To determine whether similar changes also occur after dermal exposure to this COM, pregnant rats and mice were exposed during periods of organogenesis (Days 11 to 15 of gestation). Shaved backs were painted with 0, 500, or 1500 mg/kg of the COM (control, low, or high dose, respectively); the exposed area was not occluded. Maternal weight gain during the gestation period decreased with increasing dose in rats but not in mice. Examination of rat fetuses on Day 20 of gestation showed that resorptions had occurred in more than 90% of low- and high-dose litters (vs 6% in the control group). In mice, fetal examinations on Day 18 of gestation showed that resorptions occurred in 71% of litters from both exposure groups (vs 14% in the controls). Fetal measurements indicated that both the weight and the length of rat fetuses decreased with increasing dose, but mouse fetuses were unaffected. Cleft palates, absent in the control groups, were observed in 50 to 55% of the high-dose group and 5 to 8% of the low-dose fetuses of both species. Small fetal lungs occurred in nearly 100% of the exposed rat fetuses and in 25% of the high-dose mice; the incidence of small lungs was 1% in control animals. Other variations observed in exposed groups included edema and reduced ossification in the rat and renal pelvic cavitation in the mouse.(ABSTRACT TRUNCATED AT 250 WORDS)

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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.

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Co-incubation of benzo[a]pyrene (BaP) and coal-derived complex organic mixtures has been shown to decrease the metabolism and mutagenic activity of BaP. Because of these influences, five mixtures were co-administered dermally to mice to initiate tumor development. Results from these studies demonstrated that BaP tumor-initiating activity was decreased substantially by four of the five mixtures. When one of the mixtures was separated into chemical class fractions, the polycyclic aromatic hydrocarbon (PAH) and nitrogen-containing polycyclic aromatic compound fractions were the most effective, and the aliphatic and hydroxy-PAH fractions were the least effective as inhibitors of BaP-induced tumor initiation. Binding of [3H]BaP to epidermal DNA under conditions identical to those used for tumor initiation was decreased by co-administration of all five mixtures. Calculations of the number of tumors produced/micrograms BaP bound to DNA demonstrated that co-administration of this carcinogen with the mixtures consistently increased the effectiveness of the bound BaP at producing tumors by approximately a factor of 2. The HPLC radioactivity profiles of enzyme-hydrolyzed, adducted DNA indicated that, in the presence of the mixtures, the predominant adducts were derived from BaP-diol epoxide (BPDE); however, the mixtures decreased the ratios of the anti-BPDE-deoxyguanosine to syn-BPDE-deoxy-guanosine adducts. These data indicate that the prevailing influences of the mixtures (i.e. decreased DNA binding and adduct shifts) were similar to those observed with other bioassays following co-administration of binary mixtures. Furthermore, the data demonstrate that both DNA binding and adduct profiles are important in determining the contribution of a known carcinogen to tumor initiation by complex organic mixtures.

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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.

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Relative frequencies of diethylnitrosamine (DEN)-initiated foci of altered hepatocytes appearing in response to promotion by either dietary phenobarbital or a topically applied coal-derived organic mixture (CDM) were investigated in male and female rats. The focus population was examined for two histochemical markers, elevated gamma-glutamyl transpeptidase [GG(+)] and iron exclusion [FE(-)], giving rise to 3 detectable focus phenotypes, i.e., GG(+) foci, FE(-) foci, and GG(+)/(FE(-) foci. Frequencies of the 3 phenotypes were quantitated through the use of serial frozen sectioning and computer-assisted image analysis. In agreement with our prior observations, cutaneous exposure to CDM or dietary phenobarbital promoted the expression of DEN-initiated foci. However, the current data showed that this promoting effect of CDM occurred only in females and was restricted to foci with the GG(+)/FE(-) phenotype. Dietary phenobarbital, on the other hand, promoted both the GG(+) and GG(+)/FE(-) phenotypes and was effective in both males and females, although a sex-related differential in the promoting efficiency of phenobarbital was also observed. The pronounced heterogeneity in the responses of the 3 focus phenotypes suggests that each phenotype is the consequence of a specific type of genomic alteration with a specific capacity to undergo phenotypic expression in response to a given promoting stimulus.

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Mice (CD-1) were exposed to aerosol concentrations of 0.0, 0.03, 0.14, or 0.69 mg/liter of heavy distillate (HD), a high-boiling coal liquid from the solvent-refined coal (SRC)-II process. Exposures were for 6 hr/day, 5 days/week for 13 weeks. Particle sizes ranged between 1.6 and 1.8 micron, mass median aerodynamic diameter, with a geometric standard deviation range of 1.9-2.5. Growth for high-dose males was significantly less than that of the control group. Compared to controls, weights of liver were significantly higher and those of ovaries and thymus significantly lower; these changes were significant on both absolute and relative weight bases. The number of red blood cells, volume of packed red cells, and hemoglobin concentration for animals from the high-dose group were significantly lower than those of controls. Microscopic examination of organ sections showed focal hepatic necrosis and nonspecific hepatopathy. Additionally, olfactory epithelial degeneration occurred in a dose-dependent manner. Results from this study indicated that exposure to HD caused adverse effects at the high dose and that these changes were either less severe or absent in middle-dose group mice. Comparison of these results with those for rats indicated that with rats the biological effects were more severe and present at lower doses than was observed for mice.

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To investigate the metabolism of 241Am as affected by pregnancy and lactation, female rats were injected with 5 muCi of 241Am intravenously while nulliparous, pregnant or lactating. The females and subsequent litters were killed at various times after injection to determine 241Am distribution and retention. The temporal relationship between injection and pregnancy influenced the tissue retention of 241Am in both dams and progeny. The half-time of 241Am in livers of pregnant or lactating rats was more than twice that of nulliparous rats, although the initial uptake was approximately 50% of the activity in all groups. Both spleen and femur accumulated more 241Am at 7-10 weeks after injection than at earlier times, but this increase could not be related to pregnancy. Approximately 10 times more 241Am was transferred to offspring from dams that were lactating when exposed than was transferred via the placenta when exposure occurred late in gestation. Furthermore, more 241Am was transmitted to the progeny via milk if exposure of the dam occurred during lactation rather than during pregnancy.

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Coal liquids have been evaluated in a variety of short-term toxicological assays; however, few studies have been conducted to determine the systemic effects after inhalation exposure to these materials. To extend the data base on potential health effects from coal liquefaction materials, we performed a study with solvent refined coal (SRC)-II heavy distillate (HD). Fischer-344 rats were exposed for 6 hr/day, 5 days/week for 5 or 13 weeks to an aerosol of HD (boiling range, 288 to 454 degrees C) at concentrations of 0.69, 0.14, 0.03, or 0.0 mg/liter of air for the high, middle, low, and control groups, respectively. Survival through 13 weeks of exposure was greater than 90% for all groups; body weights for exposed animals were decreased in a dose-dependent manner. Significant increases in liver weights and decreases in thymus and ovary weights were observed for treated animals compared with controls. There were also significant treatment-related decreases in erythrocytes, hemoglobin, volume of packed red blood cells, lymphocytes, eosinophils, and total white blood cells. After 5 weeks of exposure serum cholesterol concentrations increased in a dose-dependent manner for both sexes and serum triglyceride amounts decreased for males but not for females. After 13 weeks of exposure, high-dose animals had significant increases in cholesterol (males only), triglycerides, blood urea nitrogen, and serum glutamic pyruvic transaminase (SGPT; males) and significant decreases in albumin, SGPT (females), and lactate dehydrogenase (LDH). Examination of bone-marrow preparations from exposed animals demonstrated consistent decreases in the degree of cellularity, suggesting that this organ is a target for HD. Microscopic evaluation of organ sections indicated exposure-related changes for nasal mucosa, pulmonary macrophages, thymus, liver, kidney, bone marrow, ovaries, and cecum. Results from this study indicated dose-dependent increases in the severity of the lesions observed, with few effects in the low-exposure group that were attributable to the exposure.

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The promotion of preneoplastic hepatocyte foci was observed in rats neonatally initiated by a single intraperitoneal injection of benzo[a]pyrene (BP) or diethylnitrosamine (DEN) and exposed, from weaning, to repeated topical applications of coal-derived complex organic mixtures that are carcinogenic for mouse skin. Topical application of these mixtures in the absence of prior initiation did not cause significant induction of hepatocyte foci. These observations indicate the advantage of the neonatal rat hepatocarcinogenesis system for detecting promoting activity in carcinogenic mixtures and identify the existence of systemic tumorigenic risk from cutaneous contact with promoting agents.

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In this study, methodologies developed for the analysis of synthetic fuel products were applied to the coal tar fractions isolated from coal tar-based pharmaceutical products. A pharmaceutical stock solution of 20% coal tar in alcohol, a 50% coal tar bath emulsion and a 4.3% coal tar shampoo were studied. The toxicology and chemical composition of the coal tar fractions isolated from these materials were compared with an industrial coal tar and with a direct-liquefaction coal liquid product. The coal tars and coal liquid product were fractionated into chemical classes by alumina column chromatography and individual components were identified and quantitated by high-resolution gas chromatography. The microbial mutagenicity of these materials was measured against S. typhimurium, TA 98. In addition, the industrial coal tar, coal-liquid product, and coal tar isolate from the 20% coal tar in alcohol solution were tested for initiating activity in an initiation/promotion mouse skin painting assay for carcinogenicity. The chemical compositions of the coal tar-based therapeutic agents, the industrial coal tar and direct-liquefaction coal liquid were similar. With the exception of the 50% bath emulsion, the microbial mutagenicity and tumor-initiating activity in mouse skin for those materials tested were also similar.

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The chemical composition and microbial mutagenicity of aerosols generated by nebulizing two coal oils (solvent refined coal [SRC]-I process solvent [PS] and SRC-II heavy distillate) were found to vary with particle size. Significant quantities of the most volatile components of PS were also present as vapors. Evaporation and condensation processes in oil deposited on surfaces as well as in the aerosol are believed to be important in determining the observed composition changes. Complete physical and chemical characterization of the aerosol should be included in inhalation studies of complex materials since the animals may be exposed to material of quite different composition than that placed in the generator initially.

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Narrow temperature range distillates from biologically active solvent refined coal-I and -II heavy-end coal liquids were fractionated according to chemical class and assayed for initiation of skin carcinogenesis in CD-1 mice. In addition, instrumental chemical analyses were performed on the distillates and their chemical fractions. Results showed that initiation activity in these complex fuel mixtures could be segregated both by boiling point and chemical class. Neutral polycyclic aromatic hydrocarbon fractions were the most active of the chemical classes, with some initiating activity being shown by nitrogen-containing polycyclic aromatic hydrocarbon. Aliphatic and hydroxylated polycyclic aromatic hydrocarbon fractions showed little or no initiating activity. For the two solvent refined coal-II distillates studied, initiating activity was substantially higher in the material boiling above 850 degrees F than in that boiling 800-850 degrees F, although both contained essentially the same concentrations of benzo[a]pyrene. These data indicate that the overall initiating activity of these complex mixtures is highly dependent on interactions of the many chemical carcinogens and that relative concentrations of known carcinogenic polycyclic aromatic hydrocarbons, such as benzo[a]pyrene and dimethylbenz[a]anthracene, are not the sole determinants of initiating activity.

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A fuel-oil blend (FOB) and its hydrotreated product from the solvent-refined coal (SRC) II process were evaluated for their mutagenic and carcinogenic potential. The FOB was highly active in both cellular assays, as well as in animal (skin-painting) studies. Cell-transforming and mutagenic activities of hydrotreated FOB were consistently found to be lower than for untreated FOB. Finally, while most of the initiating activity (in the animal assay) was lost following hydrotreatment, the data indicate that the hydrotreated FOB still had significant skin-tumor-promoting activity.

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High-boiling coal liquids from the solvent-refined coal-I and -II (SRC-I, -II) processes, respectively, were fractionally distilled. In the case of SRC-I process solvent (PS), 50 degrees F distillation cuts were obtained between 550 and 850 degrees F, while for the SRC-II material, the 50 degrees F cuts were only obtained between 700 and 850 degrees F. These cuts, as well as the parent material, were tested for their ability to initiate skin tumors by applying a single dose (25 mg) to the shaved backs of Charles River female CD-1 mice. After 2 weeks, the mice received twice weekly applications of 5 micrograms of the promoter, phorbol myristate acetate. Only a few tumors were found for SRC-I fractions boiling below 700 degrees F; tumor-initiating activity increased as the boiling point increased. A similar increase in response with increasing boiling point was seen for the SRC-II cuts. The initiating activities for the parent materials were similar to those observed for their respective 800 to 850 degrees F cuts.

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Newborn (1-2 days old) and weanling (6 wk old) miniature pigs were injected intravenously with 239Pu citrate. Animals from each age group were killed at intervals over a 28-day period to obtain distribution and retention data. The most notable difference between the two age groups was in hepatic deposition and retention. One day after injection, the plutonium content of the liver in neonates was only one-third that in weanling pigs (4.3 vs 13.9% of administered 239Pu). Deposition and retention were not markedly different in individual skeletal components. Cumulative excretion during the first 7 days after injection was the same for each group--1.4% of the injected plutonium.

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The biological activity of materials produced in the direct liquefaction of coal is being assessed by a variety of test systems. In this study, the pulmonary toxicity of process solvent (PS) from the solvent refined coal-I (SRC-I) process was determined by histamine aerosol challenge tests and pulmonary function and morphologic evaluations. Guinea pigs inhaled aerosols of PS (boiling range, 230 to 450 degrees C) for 6 hr/day, 5 day/week, for up to 12 days in three different experiments. In the first experiment, 8-week-old animals inhaled 0 (controls), 0.15, or 0.60 mg/liter PS aerosols with a mass median aerodynamic diameter (MMAD) of 1.3 micrometer. Exposure to 0.15 mg/liter PS for 12 days resulted in depressed weight gain and marked hypersensitivity to inhaled histamine compared with sham-exposed control animals. Four of five animals exposed to 0.6 mg/liter PS died of respiratory failure during exposure. During the second experiment, 14-week-old animals inhaled 0 (controls) or 0.19 mg/liter PS (MMAD, 1.3 microns) for 1, 3, or 12 days. Hypersensitivity to aerosolized histamine occurred only after 12 days exposure to PS aerosols. At that time, morphologic lung evaluations showed mild to moderate pneumonitis and accumulation of exudate in bronchioles of PS-exposed animals. In the third experiment, pulmonary function evaluations were conducted on 4-week-old animals exposed to 0 (controls) or 0.19 mg/liter PS for 8 days. Functional changes measured in these animals (compared to controls) included increased gas trapping at low lung volumes, decreased quasi-static compliance, and decreased diffusion capacity of the lung for carbon monoxide. These studies showed that measurable changes in lung function were produced in guinea pigs after 8 to 12 days exposure to 0.15 or 0.19 mg/liter PS and that exposure to PS affected weight gain only in younger animals (4 and 8 weeks old) but not in 14-week-old animals.

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Fractions derived from solvent-refined coal-II (SRC-II) heavy distillate (HD) were tested for their skin tumor initiating activity. Basic (BF), basic tar (BTF), neutral tar (NTF) and polynuclear aromatic (PNA) fractions were prepared from HD by solvent extraction. These fractions were tested for their initiating activities by applying a single dose to the shaved back of male, CD-1 mice (Charles River, Portage, MI). Positive control groups were initiated with either dimethylbenz[a]anthracene (DMBA) or benzo[a]pyrene (BaP). Two weeks after initiation, all mice received twice weekly applications of 5 micrograms of phorbol myristate acetate (PMA) for a period of 24 weeks. Papillomas were noted and recorded for each animal at the time of PMA application. Heavy distillate and its fractions all showed initiating activity. However, the incidence of mice with tumors, the rate of tumor appearance and the total number of tumors varied with the test material. The tumor responses after initiation with HD,NTF and BTF were similar to that found with BaP, but lower than that with DMBA. Somewhat lower activity was found for BF and PNA. Even lower activity was found with a distillate boiling from 800 to 850 degrees F and no activity was found with a 300 to 700 degrees F distillate. These data are in general agreement with the results of long-term, skin painting assays, suggesting that initiation/promotion (I/P) may be useful for studying the tumorigenicity of coal-derived materials.

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Studies with a variety of chemically purified substances have suggested that induction of the enzyme ornithine decarboxylase (ODC) in mouse epidermal cells may be a reliable indicator of neoplastic transformation. In an effort to extend these observations on ODC to chemically complex materials, we examined ODC induction by carcinogenic and non-carcinogenic mixtures and compared these results with tumorigenicity data for these materials. For these studies several boiling range fractions and several solvent-derived subfractions from two solvent-refined coal processes (SRC-I and SRC-II) were evaluated for their ability to induce ODC. Single applications of heavy distillate (HD), the SRC-II high-boiling fraction and a potent mouse skin carcinogen, produced ODC induction kinetics which were similar to that for 12-O-tetradecanoylphorbol-13-acetate (TPA). Both HD and TPA stimulated maximal ODC activity 3-5 h after application, with epidermal ODC levels returning to basal levels within 12 h. The magnitude of ODC induction after multiple applications of HD was not as great as that observed for TPA. Single skin applications of TPA and HD also transiently elevated hepatic ODC levels 27- and 7-fold, respectively; however, liver ODC activity did not increase following multiple applications of either chemical. Further, ODC induction by HD was also dose-dependent. Relative to controls, single applications of HD and process solvent (boiling range greater than 250 degrees C) elevated ODC levels 145- to 205-fold, light distillate and light oil (boiling range less than 180 degrees C) increased ODC levels 23- to 32-fold, and middle distillate and wash solvent (boiling range 180-250 degrees C) stimulated less than 2- to 8-fold increases in ODC. Single applications of three solvent-derived subfractions of HD, which are complete carcinogens, induced 3- to 7-fold ODC elevations over background levels; multiple applications of two of these subfractions elevated ODC levels 10- to 22-fold. Of the complex mixtures evaluated during this study, all complete carcinogens induced ODC; however, the magnitude and temporal pattern of induction varied with the material tested.

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On days 12-16 of gestation pregnant rats were exposed to heavy distillate (HD), the highest-boiling material derived from the solvent refined coal-II (SRC-II) process, and the litters were examined at day 21. Adverse biological effects were observed in the group of animals exposed to an aerosol concentration of 0.66 mg 1-1 [1.8 microgram, mass medium aerodynamic diameter (MMAD)]; groups of animals exposed to lower aerosol concentrations (0.084 and 0.017 mg 1-1) were largely unaffected. Embryo lethality during mid- and late gestation appeared attributable to the coal liquid exposure. Fetuses from pregnant rats in the high exposure group were smaller in weight and length than fetuses from control animals, and skeletal ossification was reduced. Increased incidences of small lungs and cleft palate were observed in fetuses from the high exposure group. Pregnant rats in the high-exposure group gained less weight than controls during gestation; the reduced weight gain was accounted for by the reduced size of the fetuses and placentas. Even though maternal body weight (exclusive of the products of conception) was unaffected by the exposure, the weights of the maternal thymus, lung and spleen were altered in the high exposure group.

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