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Publications (49)101.69 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Various methods have been proposed as a basis for cancer hazard labelling of petroleum products. The Institute of Petroleum analytical method termed IP 346/80 was recently recommended to the European Union as the preferred method for this purpose. In this report we compare IP 346/80 with several other predictors of dermal carcinogenicity, including the Mobil PAC Method, the Modified Ames Test (ASTM Method E 1687-95), and the -postlabelling assay for DNA adducts. Oils for assay were selected from a repository of samples previously subjected to mouse skin-painting bioassay. 120 oils were tested in the Modified Ames Assay, 57 by the Mobil PAC Method, 50 by Method IP 346/80, and 48 by the postlabelling procedure. The ability of each assay to distinguish between carcinogenic and noncarcinogenic oils was examined at various suggested discriminators, e.g. Mutagenicity Indices (MI) of 1.0 and 2.0, 3-7 ring PAC contents of 1% and 2% (w/w), and IP 346/80 DMSO-extractables of 2% and 3% (w/w). Various adduct levels were tested for maximum discrimination between carcinogenic and noncarcinogenic oils. The accuracy of each method is reported.
    Polycyclic Aromatic Compounds 03/2008; 11:201-210. DOI:10.1080/10406639608544667 · 0.83 Impact Factor
  • Timothy A. Roy, Anthony J. Kriech, Carl R. Mackerer
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    ABSTRACT: Bitumen fume condensate was obtained from the headspace vapors of a bitumen storage tank containing a lightly oxidized paving-bitumen for the purpose of developing an in vitro procedure to estimate the percutaneous absorption, through human skin, of the very low levels of polycyclic aromatic compounds found in the condensate. The Fraunhofer Institute of Toxicology and Medicine provided the fume condensate and analyses of the individual polycyclics present. Heritage Research Group provided analyses of total 3–6 ring polycyclics. Sections of human back skin were sliced with a dermatome to a thickness of 250 μ m, and 1-inch circular pieces were mounted in 6 Franz diffusion cells. Tissue integrity was assured by electrical resistance measurement. Neat condensate was applied to the stratum corneum at “infinite dose” (200 μ l) while the dermis was in direct contact with a receptor fluid consisting of an aqueous solution of polyoxyethylene 20 oleyl ether. Receptor fluids were sampled at 12 intervals over 48 hours, and analyzed by an HPLC system equipped with a variable wavelength detector and a fluorescence detector connected in series. The UV detector was generally operated at 254 nm, and the fluorescence detector at ex360nm/em400nm, 18 nm bandpass. The mobile phase was a 60–100% acetonitrile/water gradient. Penetration rates of anthracene, fluoranthene-pyrene, and total 3–6 ring polycyclic aromatic compounds (PAC) were measured. The neat condensate was 32.7 μ g/g anthracene, 7.4 μ g/g fluoranthene, 7.3 μ g/g pyrene, and 1.8 mg/g total 3–6 ring PAC. The rates of dermal penetration (ng/cm2/hr ± SD) were: anthracene 6.5 ± 0.9; fluoranthene-pyrene 1.8 ± 0.3; and 3–6 ring PAC 120 ± 30. Percentages of applied dose absorbed were: anthracene 5.3%, fluoranthene-pyrene 3.3%, and 3–6 ring PAC 1.8%. The apparent permeability coefficient Kp (Kp = flux rate/applied concentration) for anthracene was 2 × 10− 4 cm/hr. These results demonstrate that penetration of PAC, at the low concentrations found in bitumen fume condensates, can be measured by an appropriately designed in vitro method. Rates of PAC percutaneous absorption will be further evaluated in the future with other fume condensates obtained from several different straight run paving asphalts.
    Journal of Occupational and Environmental Hygiene 05/2007; 4(S1):137-143. DOI:10.1080/15459620701334814 · 1.21 Impact Factor
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    ABSTRACT: Petroleum base oils (petroleum mineral oils) are manufactured from crude oils by vacuum distillation to produce several distillates and a residual oil that are then further refined. Aromatics including alkylated polycyclic aromatic compounds (PAC) are undesirable constituents of base oils because they are deleterious to product performance and are potentially carcinogenic. In modern base oil refining, aromatics are reduced by solvent extraction, catalytic hydrotreating, or hydrocracking. Chronic exposure to poorly refined base oils has the potential to cause skin cancer. A chronic mouse dermal bioassay has been the standard test for estimating carcinogenic potential of mineral oils. The level of alkylated 3-7-ring PAC in raw streams from the vacuum tower must be greatly reduced to render the base oil noncarcinogenic. The processes that can reduce PAC levels are known, but the operating conditions for the processing units (e.g., temperature, pressure, catalyst type, residence time in the unit, unit engineering design, etc.) needed to achieve adequate PAC reduction are refinery specific. Chronic dermal bioassays provide information about whether conditions applied can make a noncarcinogenic oil, but cannot be used to monitor current production for quality control or for conducting research or developing new processes since this test takes at least 78 weeks to conduct. Three short-term, non-animal assays all involving extraction of oil with dimethylsulfoxide (DMSO) have been validated for predicting potential carcinogenic activity of petroleum base oils: a modified Ames assay of a DMSO extract, a gravimetric assay (IP 346) for wt. percent of oil extracted into DMSO, and a GC-FID assay measuring 3-7-ring PAC content in a DMSO extract of oil, expressed as percent of the oil. Extraction with DMSO concentrates PAC in a manner that mimics the extraction method used in the solvent refining of noncarcinogenic oils. The three assays are described, data demonstrating the validation of the assays are shown, and test results of currently manufactured base oils are summarized to illustrate the general lack of cancer hazard for the base oils now being manufactured.
    Applied Occupational and Enviromental Hygiene 12/2003; 18(11):890-901. DOI:10.1080/10473220390237467
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    ABSTRACT: Gasoline (CAS 86290-81-5) is one of the world's largest volume commercial products. Although numerous toxicology studies have been conducted, the potential for reproductive toxicity has not been directly assessed. Accordingly, a two-generation reproductive toxicity study in rats was conducted to provide base data for hazard assessment and risk characterization. The test material, vapor recovery unit gasoline (68514-15-8), is the volatile fraction of formulated gasoline and the material with which humans are most likely to come in contact. The study was of standard design. Exposures were by inhalation at target concentrations of 5000, 10 000, and 20 000 mg/m(3). The highest exposure concentration was approximately 50% of the lower explosive limit and several orders of magnitude above anticipated exposure during refueling. There were no treatment-related clinical or systemic effects in the parental animals, and no microscopic changes other than hyaline droplet nephropathy in the kidneys of the male rats. None of the reproductive parameters were affected, and there were no deleterious effects on offspring survival and growth. The potential for endocrine modulation was also assessed by analysis of sperm count and quality as well as time to onset of developmental landmarks. No toxicologically important differences were found. Therefore, the NOAEL for reproductive toxicity in this study was > or =20 000 mg/m(3). The only systemic effects, in the kidneys of the male rats, were consistent with an alpha-2 u-globulin-mediated process. This is a male rat-specific effect and not relevant to human health risk assessment.
    Reproductive Toxicology 07/2000; 14(4):337-53. DOI:10.1016/S0890-6238(00)00085-X · 2.77 Impact Factor
  • TA Roy, G. R. Blackburn, C. R. Mackerer
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    ABSTRACT: Processes for reducing the mutagenicity of refinery streams and coal tars containing polynuclear aromatic compounds (PAC) are described. The investigation was based on the supposition that the reduced mutagenic activity of some refinery streams (relative to cracked stocks and coal tars) was related to the degree of alkylation of the PAC stream components. Much of the development work was carried out using benzo[a]pyrene (BaP) as a model surrogate for the PAC responsible for the mutagenic potency of refinery streams and coal tars. Using Friedel-Crafts procedures, the mutagenic activity of a number of refinery streams and coal tar products was significantly reduced or completely eliminated when reacted with a C3-, C4-, or C5-alkylating agent. Recent work has turned toward adapting the laboratory-based chemistry to refinery-based chemistry using heterogeneous catalysis (acid clay/pillared catalysts/zeolites).
    Polycyclic Aromatic Compounds 12/1999; 14:241-251. DOI:10.1080/10406639908019130 · 0.83 Impact Factor
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    C R Mackerer, M L Barth, AJ Krueger, B Chawla, TA Roy
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    ABSTRACT: Neurotoxicity of tricresyl phosphates (TCPs) and jet engine oil (JEO) containing TCPs were evaluated in studies conducted in both rat and hen. Results for currently produced samples ("conventional" and "low-toxicity") were compared with published findings on older samples to identify compositional changes and relate those changes to neurotoxic potential. Finally, a human risk assessment for exposure by oral ingestion of currently produced TCPs in JEO at 3% (JEO + 3%) was conducted. TCPs and certain other triaryl phosphates administered as single doses inhibited brain neuropathy target esterase (B-NTE; neurotoxic esterase) in the rat and the hen (hen 3.25 times as sensitive), and both species were deemed acceptable for initial screening purposes. Neither rat nor hen was sensitive enough to detect statistically significant inhibition of B-NTE after single doses of IEO + 3% "conventional" TCP. Subacute administration of 2 g/kg/d of JEO + 3% "conventional" TCP to the hen produced B-NTE inhibition (32%), which did not result in organophosphorus-induced delayed neurotoxicity (OPIDN). Subchronic administration of JEO + 3% TCP but not JEO + 1% TCP at 2 g/kg/d produced OPIDN. Thus, the threshold for OPIDN was between 20 and 60 mg "conventional" TCP/kg/d in JEO for 10 wk. The current "conventional" TCPs used in JEO and new "low-toxicity" TCPs now used in some JEO are synthesized from phenolic mixtures having reduced levels of ortho-cresol and ortho-xylenols resulting in TCPs of very high content of meta- and para-substituted phenyl moieties; this change in composition results in lower toxicity. The "conventional" TCPs still retain enough inhibitory activity to produce OPIDN, largely because of the presence of ortho-xylyl moieties; the "low-toxicity" TCPs are largely devoid of ortho substituents and have extremely low potential to cause OPIDN. The TCPs produced in the 1940s and 1950s were more than 400 times as toxic as the "low-toxicity" TCPs produced today. Analysis of the doses required to produce OPIDN in a subchronic hen study suggests that the minimum toxic dose of "conventional" TCP for producing OPIDN in a 70-kg person would be 280 mg/d, and for JEO containing 3% TCP, 9.4 g/d. Food products could be inadvertently contaminated with neat "conventional" TCP but it is unlikely that food such as cooking oil would be contaminated with enough JEO + 3% TCP to cause toxicity. Further, at the dosage required for neurotoxicity, it would be virtually impossible for a person to receive enough JEO + 3% TCP in the normal workplace (or in an aircraft) to cause such toxicity. There is no record of a JEO formulated with the modern "conventional" TCP causing human neurotoxicity.
    Journal of Toxicology and Environmental Health Part A 08/1999; 57(5):293-328. DOI:10.1080/009841099157638 · 1.83 Impact Factor
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    ABSTRACT: Coal, which contains significant amounts of water, can be ground and dried to produce an efficient fuel for electric power plants; however, spontaneous combustion can occur in the dried coal. Liquid petroleum hydrocarbons inhibit this combustion, but not all petroleum streams are effective. No. 6 fuel oil, a readily available and inexpensive stream, provides an effective coating, but the carcinogenic potential of coal particles treated with No. 6 fuel oil, which contains polynuclear aromatic hydrocarbons (PNAs), was undefined. As part of the assessment process, a series of studies was conducted to compare this treated coal with similar particles (petroleum coke) that had been tested by chronic inhalation in monkeys and rats. The amounts of PNAs in petroleum coke and treated coal were compared in extraction studies; the treated coal had only two-thirds of the organics extractable with benzene compared with coke and only 7% as much of the 3-7 ring PNAs, the likely tumorigenic compounds. In addition, the analytical profile of 3-7 ring PNAs was of lower molecular weights in the coal treated with fuel oil. The mutagenicity of extracts from treated coal was much less than with petroleum coke and markedly less than that of No. 6 fuel oil itself. The percutaneous absorption of 3H-benzo(a)pyrene from both particles and from their benzene extracts, as measured in vitro, was approximately eight times greater with petroleum coke than with treated coal. Based on these preliminary results, there is no evidence suggesting that the treated coal would pose any greater carcinogenic risk than petroleum coke.
    AIHAJ 03/1998; 59(2):90-5. DOI:10.1080/15428119891010343
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    ABSTRACT: A structure-activity relationship (SAR) of the in vitro percutaneous absorption of polycyclic aromatic hydrocarbons (PAH) is described. The data set consisted of 60 three to seven ring PAH. Over 50 numeric descriptors were generated from the modeled molecular structures. Computer aided methods were used to evaluate descriptors and develop linear expressions relating the percent of dermally applied PAH dose absorbed through skin (PADA) to PAH structure. Three regression models with one and two variables were developed. The log octanol/water partition coefficient (log P) was the most important variable in determining percutaneous absorption. An inverse relationship between log P and the skin penetration properties of the PAH was observed. Nearly 40 of 60 PAH tested had PADA-values within a factor of two of benzo[a]pyrene (BaP); well over 50 of 60 had PADA-values within a factor of three. The results lend support to the use of isotopically labeled BaP as a surrogate for measuring the dermal flux (in vivo and in vitro) and estimating the dermal bioavailability of PAH from complex mineral oil and coal-tar derived mixtures.
    SAR and QSAR in Environmental Research 02/1998; 9(3-4):171-85. DOI:10.1080/10629369808039155 · 1.92 Impact Factor
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    ABSTRACT: Two crude oils, differing in viscosity (V) and nitrogen (N) and sulfur (S) content, were evaluated for pre- and postnatal developmental toxicity. In Crude I (low V, low N, low S) studies, the material was applied neat to the clipped backs of pregnant rats at dose levels of 0, 125, 500, 1000 (postnatal only), and 2000 (prenatal only) mg/kg. In Crude II (high V, high N, moderate S) studies, the oil was applied similarly but at dose levels of 0, 30, 125, and 500 mg/kg. Rats were exposed to the crude oils on gestation days (GD) 0-19; application sites were not covered. "Prenatal" rats were killed on GD 20. "Postnatal" rats were allowed to deliver naturally; surviving dams and litters were killed 3-4 wk postpartum. Both crude oils produced maternal and developmental toxicity. Adverse fetal effects included increased in utero death, decreased body weight, and reduced ossification of skeletal elements. Parturition was delayed in Crude II dams at 500 mg/kg. The 4-d viability index was decreased in all Crude II-exposed groups. Pup body weights were decreased by each oil, but at the high dose only. Prenatal effects are probably related to polynuclear aromatic compounds (PAC) found in petroleum. The cause(s) of delayed parturition and postnatal toxicity have not been determined.
    Journal of Toxicology and Environmental Health 10/1997; 52(1):79-93. DOI:10.1080/00984109708984054 · 1.81 Impact Factor
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    ABSTRACT: An in vitro system was utilized to measure DNA adduct-forming ability of petroleum oils and oil coal tar mixtures to define correlations between DNA adduct levels and their mutagenic potencies. The system consisted of reaction of dimethyl sulfoxide extracts of oils with calf thymus DNA in the presence of Aroclor-induced hamster liver microsomes for 30 min. Following DNA extraction, DNA adducts were measured by the nuclease P1-enhanced postlabeling assay coupled with two-dimensional polyethyleneimine (PEI)-cellulose TLC. Thin layer plates showed putative aromatic DNA adducts, with levels ranging from 60 to 1400 adducts per 10(9) DNA nucleotides. TLC mobilities suggested adducts to be aromatic compounds containing 4 or more rings. A good correlation (coefficient of correlation = 0.91) was observed between DNA adduct levels and Salmonella mutagenicity for 19 oils. All 19 samples tested produced DNA adducts. To expedite the TLC procedure, adducts were resolved by one-dimensional TLC and the radioactivity measured using a mechanical scanner. Results were comparable to those obtained by two-dimensional TLC and quantification after scraping. Our data show that the in vitro incubation system coupled with the postlabeling adduct assay is a useful screening method to identify mutagenic and potentially carcinogenic oils.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 09/1997; 378(1-2):89-95. DOI:10.1016/S0027-5107(97)00100-0 · 4.44 Impact Factor
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    ABSTRACT: Two crude oils, differing in viscosity (V) and nitrogen (N) and sulfur (S) content, were evaluated for systemic toxicity. In the Crude I (low V, low N, low S) study, the material was applied to the clipped backs of rats at dose levels of 0, 30, 125, and 500 mg/kg. In the Crude II (high V, high N, moderate S) study, the oil was applied similarly at the same dose levels. The crude oils were applied for 13 wk, 5 d/wk. Exposure sites were not occluded. Mean body weight gain (wk 1-14) was significantly reduced in male rats exposed to Crude II; body weight gain of all other animals was not adversely affected by treatment. An increase in absolute (A) and relative (R) liver weights and a decrease in A and R thymus weights were observed in male and female rats exposed to Crude II at 500 mg/kg; only liver weights (A and R) were adversely affected in male and female rats exposed to Crude I. In general, there was no consistent pattern of toxicity for serum chemistry endpoints; however, more parameters were adversely affected in Crude II-exposed female rats than in the other exposed groups. A consistent pattern of toxicity for hematology endpoints was observed among male rats exposed to Crude I and male and female rats exposed to Crude II. Parameters affected included: Crudes I and II, red blood cell count, hemoglobin, and hematocrit; Crude II, platelet count. Microscopic evaluation of tissues revealed the following treatment-related findings: Crude I, treated skin, thymus, and thyroid; Crude II, bone marrow, treated skin, thymus, and thyroid. The LOEL (lowest observable effect level) for skin irritation and systemic toxicity (based on marginal effects on the thyroid) for both crude oils was 30 mg/kg; effects were more numerous and more pronounced in animals exposed to Crude II. Systemic effects are probably related to concentrations of polycyclic aromatic compounds (PAC) found in crude oil.
    Journal of Toxicology and Environmental Health 08/1997; 51(4):387-99. DOI:10.1080/00984109708984032 · 1.81 Impact Factor
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    M H Feuston, C E Hamilton, C R Mackerer
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    ABSTRACT: Syntower bottoms (STB) was evaluated for subchronic and developmental toxicity. In the subchronic study, undiluted STB was applied on the shaved backs of male and female rats at dose levels of 0, 8, 30, 125, and 500 mg/kg for 13 weeks, 5 days per week. Exposure sites were not covered. In the developmental toxicity study, STB was similarly applied, but to pregnant rats at dose levels of 0, 8, 30, and 125 mg/kg on Gestation Days 0-19. In addition, 4 mg/kg was dosed as 8 mg/kg every other day, starting on Gestation Day 0, and 500 mg/kg was dosed on Gestation Days 10-12. Evidence of toxicity observed in the subchronic study included death, decreased body weights, aberrant serum chemistry and hematology values, altered organ weights, and histopathologic changes in a variety of organs. A no observed adverse effect level for systemic toxicity could not be established. Evidence of maternal toxicity was observed at all exposure levels in the development study. Regardless of the length of the exposure period, STB was toxic to the developing conceptus. Evidence of developmental toxicity observed included increased resorptions with a concomitant decrease in litter size and reduced fetal body weights. Cleft palate was observed in fetuses exposed in utero to STB during Gestation Days 10-12 at 500 mg/kg. No evidence of teratogenicity was observed when the exposure period was throughout gestation. Ossification delays were observed in fetuses exposed in utero to STB at doses in excess of 4 mg/kg. A no observed adverse effect level for maternal and developmental toxicity could not be established.
    Fundamental and Applied Toxicology 03/1997; 35(2):166-76. DOI:10.1093/toxsci/35.2.166
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    ABSTRACT: The Zymbal gland, a sebaceous tissue associated with the ear duct of certain rodent species, is a principal target for carcinogenesis by benzene. To investigate the mechanism of induction of tumors in the rat Zymbal gland, we have developed a procedure for primary culture of epithelial cells from Zymbal gland explants so that cytogenetic analysis can be performed on this target tissue following an in vivo exposure to benzene. Cytogenetic analysis performed 45 hr after in vivo oral dosing with benzene revealed chromosome damage that occurred as a result of acute, subchronic, and chronic dosing. This damage, expressed as a dose-related increase in the frequency of micronucleated cells, was observed in Sprague-Dawley female rats over a range of benzene doses from 12.5 to 250 mg/kg/day, and in male Fischer 344 rats at doses ranging from 1 to 200 mg/kg/day. These results are consistent with the known clastogenicity of benzene in mouse bone marrow, which is also a target tissue. This study is the first report of a genotoxic effect of benzene in the rat Zymbal gland and shows that micronucleus formation may be used as a correlate for carcinogenesis induced by benzene in this target tissue.
    Environmental Health Perspectives 01/1997; 104 Suppl 6(Suppl 6):1331-6. DOI:10.2307/3433185 · 7.03 Impact Factor
  • M. H. Feuston, C. E. Hamilton, C. R. Mackerer
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    ABSTRACT: Clarified slurry oil (CSO) is the heavy residual material produced in the fluidized catalytic cracking unit of a petroleum refinery. CSO was adm in istered via gavage or dermal application to male C3H mice (10/ group) at a dose of 1000 mg/ kg/ d, 5 d/ wk, for up to 10 weeks. Interim sacrifices were performed after 2, 4, 8, and 10 weeks of treatment for orally exposed and control mice; dermally exposed mice were sacrificed after 10 weeks. Fifty percent of the “dermal” mice died prior to scheduled sacrifice. Deaths observed in the “oral” group were attributed to apparent misintubations, not to CSO exposure. Mice exposed orally for 2, 4, or 8 weeks (but not 10 weeks) exhibited significantly increased absolute (A) and relative (R) liver weights, while all “oral” mice (including those sacrificed after 10 weeks) had significantly decreased A and R thymus weights when compared to controls. “Dermal” mice had significantly increased R liver weights and significantly decreased A and R thymus weights. After 2 weeks most “oral” mice showed hepatocyte hypertrophy. A few mice showed liver necrosis. Liver findings increased in incidence and severity until 8 weeks of exposure. After 10 weeks, the liver of most “oral” mice showed the same or less discern ible morphologic pathology than was observed after 2 weeks. At 10 weeks, “dermal” mice showed the previously described liver effects, except that liver necrosis was severe, and evidence of fibrosis was observed. In summary, although CSO was hepatotoxic, “oral” mice showed signs of liver recovery after 10 weeks of exposure despite continued treatment. Thus, CSO appears to be more toxic to mice when administered dermally than orally. Humans are more likely to come into contact with these lipids by dermal rather than by oral exposure.
    International Journal of Toxicology 01/1997; 16(6):561-570. DOI:10.1080/109158197226883 · 1.23 Impact Factor
  • Timothy A. Roy, Gary R. Blackburn, Carl R. Mackerer
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    ABSTRACT: A comparison of the polynuclear aromatic compound (PAC) content and dermal carcinogenicity was made for a series of complex oil mixtures. Results showed a significant correlation (r = 0.76) between the 3–7 ring PAC content and the carcinogenic potency, as determined in a mouse skin-painting bioassay, for oil samples ranging from those with median (50% recovered) boiling points above –500°F to those with initial boiling points of –1070°F. Two variables not considered in the original correlation study, oil viscosity and oil dermal penetration rate, were subsequently measured and their correlation with the carcinogenic potency of the oils determined using simple and multiple regression techniques. Although a weak correlation was observed between oil viscosity and the dermal penetration rate of H-benzo[a]pyrene from the oils (co-linear variables), no statistically significant correlation was observed between viscosity or penetration rate and carcinogenic potency. It is suggested that the repeated dosing of mice in a two-year skin-painting bioassay results in the attainment of a steady-state concentration of the oils in the skin compartments such that the concentration of 3–7 ring PAC at the sites of cutaneous metabolism, and the concentration of carcinogenic metabolites is proportional to the 3–7 ring PAC content of the applied oil.
    Polycyclic Aromatic Compounds 11/1996; 10(1-4):333-342. DOI:10.1080/10406639608034714 · 0.83 Impact Factor
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    ABSTRACT: Solid-liquid partitioning experiments were designed to compare the sorptive properties of petroleum coke and activated charcoal with manufactured gas plant (MGP) tar residues. In addition, in vitro dermal penetration studies using human skin sections were carried out with a neat MGP tar from an MGP site and petroleum coke-MGP tar mixtures. Dermal experiments were conducted with neat MGP tar, 1:1, and 1:9 coke-MGP tar mixtures over 144 hours under infinite dose conditions (25 mg/cm skin surface) to determine the relative permeation of MGP tar components through human skin. The neat MGP tar and coke-MGP tar mixtures were fortified with H-benzo[a]pyrene prior to the dermal experiment to facilitate measurement of skin permeation. Results from the partitioning experiments showed petroleum coke to have one-third the sorptive capacity of activated charcoal. In comparison to neat MGP tar, the dermal bioavailability of the coke-MGP tar polynuclear aromatic compounds (PAC) decreased by a factor of six for the 1:1 mixture and by a factor of over 500 for the 1:9 mixture. The data can be used to estimate the dermally absorbed dose (DAD) and the chronic systemic health effect risks associated with potential dermal exposure to MGP tars at former MGP sites and to determine the required admixing ratio of coke and MGP tar to achieve acceptable risks.
    Polycyclic Aromatic Compounds 11/1996; 10(1-4):351-358. DOI:10.1080/10406639608034716 · 0.83 Impact Factor
  • M H Feuston, C R Mackerer
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    ABSTRACT: Clarified slurry oil (CSO, CAS number 64741-62-4), a refinery stream produced by processing crude oil, is a developmental toxicant when administered dermally throughout gestation to pregnant rats. The manifestations of developmental toxicity observed included embryolethality and growth retardation; evidence of teratogenicity was limited, and not conclusive. The present study was undertaken to further explore the teratogenic potential of CSO. In an attempt to limit embryolethality and thereby promote detection of terata, CSO was administered once daily for a limited period of gestation [gestation days (GD) 9-12], via dermal application, to pregnant Sprague-Dawley rats at doses of 0, 10, 100, and 1000 mg/kg. All animals were sacrificed on GD 20. Detailed examination of the dams was performed. Due to the screening nature of this investigation, fetal evaluations were limited to body weight measurements, external examinations, and evaluation of select visceral endpoints. In the dams exposed to CSO, significant decreases in body weight [absolute and gain (GD 9-13, GD 0-20)] and in the amount of food consumed were observed at 100 and 1000 mg/kg. Additional evidence of maternal toxicity observed at 1000 mg/kg included decreased absolute and relative thymus weights, increased absolute and relative liver weights, and aberrant serum chemistry. Ingestion of the test material was evident at the high dose. Developmental toxicity was observed at 1000 mg/kg and included increased embryolethality, decreased body weight, and anomalous development (cleft palate, brachydactyly, edema). Although a low incidence of abnormal fetal development was observed at 100 mg/kg, it was not conclusive that the alterations were due to CSO exposure. It is likely that three to seven-ring polycyclic aromatic compounds present in CSO were responsible for the toxic effects observed.
    Journal of Toxicology and Environmental Health 11/1996; 49(2):207-20. DOI:10.1080/009841096160934 · 1.81 Impact Factor
  • M H Feuston, C R Mackerer
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    ABSTRACT: Clarified slurry oil (CSO), syntower bottoms (STB), and distillate aromatic extract (DAE) are refinery streams produced by processing crude oil. Each of these refinery streams is rich in both hydrocarbons having carbon numbers of C20 or greater and polycyclic aromatic compounds. Available data indicate that some refinery streams are developmentally toxic (manifested primarily as increased embryolethality and growth retardation) by the dermal route of exposure. However, there is no conclusive evidence for their being teratogenic. The present studies were designed to further explore the suspected teratogenic potency of refinery streams while at the same time limiting embryolethality. To profile teratogenic effects as a function of gestation day, pregnant rats received a single oral dose (2000 mg/kg) of CSO, STB, or DAE on one of gestation days (GD) 11-14; DAE and STB were also administered on GD 15. To profile effects as a dose response function, rats received a single oral dose of CSO, DAE, or STB on GD 12 at 125, 500, and 2000 mg/kg. Control animals were similarly treated but were administered tap water. On GD 20, dams were necropsied and the fetuses evaluated for normal development. In general, evidence of maternal toxicity (i.e., decreased body weight gain, decreased thymus weight) was observed at doses greater than or equal to 500 mg/kg. For each refinery stream tested, the incidence of resorption was greatest on GD 11. A common pattern of fetal malformations was observed for all of the refinery streams tested and included cleft palate, diaphragmatic hernia, and paw and tail defects. The incidence and type of malformation observed were influenced by the gestation day of exposure. The incidences of external and skeletal malformations were greatest on GD 11 and 12 for fetuses exposed to CSO; on GD 13 and 14, the incidence of malformation was comparable for CSO- and STB-exposed fetuses. The incidence of visceral anomalies was greatest on GD 11-13 for fetuses exposed to CSO and STB; on Gestation D 14, the incidence was comparable for each of the refinery streams tested. In general, the ability to produce adverse effects on development was greatest for CSO and least for DAE. Effects produced by STB were comparable to or less severe than those observed for CSO.
    Journal of Toxicology and Environmental Health 10/1996; 49(1):45-66. DOI:10.1080/009841096160989 · 1.81 Impact Factor
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    ABSTRACT: Methyl tertiary-butyl ether (MTBE), which is added to gasoline as an octane enhancer and to reduce automotive emissions, has been evaluated in numerous toxicological tests, including those for genotoxicity. MTBE did not show any mutagenic potential in the Ames bacterial assay or any clastogenicity in cytogenetic tests. However, it has been shown to be mutagenic in an in vitro gene mutation assay using mouse lymphoma cells when tested in the presence, but not in the absence, of a rat liver-derived metabolic activation system (S-9). In the present study, MTBE was tested to determine if formaldehyde, in the presence of the S-9, was responsible for the observed mutagenicity. A modification of the mouse lymphoma assay was employed which permits determination of whether a suspect material is mutagenic because it contains or is metabolized to formaldehyde. In the modified assay, the enzyme formaldehyde dehydrogenase (FDH) and its co-factor, NAD+ are added in large excess during the exposure period so that any formaldehyde produced in the system is rapidly converted to formic acid which is not genotoxic. An MTBE dose-responsive increase in the frequency of mutants and in cytotoxicity occurred without FDH present, and this effect was greatly reduced in the presence of FDH NAD+. The findings clearly demonstrate that formaldehyde derived from MTBE is responsible for mutagenicity of MTBE in the activated mouse lymphoma assay. Furthermore, the results suggest that the lack of mutagenicity/clastogenicity seen with MTBE in other in vitro assays might have resulted from inadequacies in the test systems employed for those assays.
    Proceedings of The Society for Experimental Biology and Medicine 10/1996; 212(4):338-41. DOI:10.3181/00379727-212-44023
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    M H Feuston, C E Hamilton, C R Mackerer
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    ABSTRACT: Distillate aromatic extract (DAE) was evaluated for subchronic and developmental toxicity. In the subchronic study, undiluted DAE was applied on the shaved backs of male and female rats at dose levels of 0, 30, 125, 500, and 1250 mg/kg for 13 weeks, 5 days per week. Exposure sites were not covered. In the developmental toxicity study, DAE was similarly applied, but to pregnant rats at dose levels of 0, 8, 30, and 125 mg/kg on Gestation Days 0-19, 500 mg/kg on Gestation Days 0-16, and 1000 mg/kg on Gestation Days 10-12. Evidence of toxicity observed in the subchronic study included death, decreased body weights, aberrant serum chemistry and hematology values, altered organ weights, and histopathologic changes in a variety of organs. Regardless of the length of the exposure period, DAE was toxic to the developing conceptus. Evidence of developmental toxicity observed included increased resorptions and reduced fetal body weights. Cleft palate and ossification delays were observed in fetuses exposed in utero to DAE on Gestation Days 10-12, but not when exposure spanned all (Gestation Days 0-19) or most (Gestation Days 0-16) of gestation.
    Fundamental and Applied Toxicology 05/1996; 30(2):276-84.