bluuebunny/crossref_metadata_2025 huggingface dataset:
Studies By the National Toxicology Program On Di(2-Ethylhexyl)Phthalate
Authors: Melnick Ronald L. , Morrissey Richard E. , Tomaszewski Konrad E.
Published: September 2013

In a 2-year feed study previously reported by the National Toxicology Program (NTP), the plasticizer di(2-ethylhexyl)phthalate (DEHP) was found to produce increased incidences of hepatocellular neoplasms in both sexes of Fischer 344 (F344) rats and B6C3F1 mice. Further studies by the NTP on this chemical have investigated its genotoxicity, dermal absorption, reproductive and developmental toxicity, and biochemical mechanism of action. DEHP was not mutagenic in Salmonella typhimurium (strains TA98, TA100, TA1535 or TA1537), in L5178Y mouse lymphoma cells, or in Drosophila melanogaster. DEHP did not induce chromosomal aberrations, but did cause a marginal dose-related increase in sister chromatid exchanges in CHO cells. In a dermal absorption study, DEHP was not absorbed well through the skin of F344 rats. In a fertility assessment study, DEHP was shown to be a reproductive toxicant in both male and female CD-1 mice. The teratogenic potential of DEHP was evaluated in F344 rats and CD-1 mice. In the rat study, there were no significant differences in percent fetuses malformed between control and treatment groups, even at dose levels (1.0, 1.5 and 2.0%) which produced significant maternal and fetal toxicity. In the mouse study, the incidence of fetuses with malformations was significantly increased at dose levels which produced maternal and/or fetal toxicity (0.10 and 0.15%), and at a dose level (0.05%) which did not cause maternal or fetal toxicity. The no-observed effect level for developmental toxicity in mice was 0.025% DEHP. Kinetic data on the rates of formation of H2O2 by peroxisomal palmitoyl CoA oxidase, and of degradation of H2O2 by catalase, was used to estimate in vitro steady-state H2O2 concentrations during peroxisofnal oxidation of palmitoyl CoA. Increases in steady-state H 2O2 in liver homogenates of rats treated with DEHP, di(2-ethylhexyl)adipate, or nafenopin, a hypolipidemic drug, correlated well with the carcinogenic potential of these cheniicals determined in previous carcinogenicity studies, and are consistent with but not definitive evidence for the involvement of peroxisome proliferation in the hepatocarcinogenesis of these compounds.
In Vivo Studies On the Mechanism of Di(2-Ethylhexyl)Phthalate Carcinogenesis
Authors: Popp James A. , Garvey Linda K. , Cattley Russell C.
Published: September 2013

In a study sponsored by the National Toxicology Program, di(2-ethylhexyl)phthalate (DEHP) fed in the diet at 1.2% significantly increased the incidence of female rats with hepatocellular carcinomas. Extensive evaluation of DEHP for carcinogenicity has yielded negative results. The present investigations were designed to elucidate the mechanism of DEHP hepatocarcinogenesis under the conditions of the original bioassay.

Short-term studies designed to evaluate the promoting capability of DEHP, when administered after initiation, were negative when livers of female Fischer-344 rats were evaluated using multiple histochemical stains to identify foci of cellular alteration. Two different protocols were used to evaluate the initiating potential of DEHP in the liver using histochemically defined foci as the endpoint. In both experiments the results were negative. Chronic exposure to DEHP at 1.2% in the diet for 2 years resulted in elevation of hepatic peroxisomal enzymes while DNA replication, an indication of cell proliferation, was not affected in hepatocytes. The number of foci was not elevated in the DEHP group compared to the controls, even though a low incidence of rats with liver tumors occurred in the treated group.

The results of this series, as well as other published results, suggest that DEHP and other peroxisomal proliferating chemicals have unique effects on the development of hepatic neoplasms. The absence of altered foci after chronic administration or in initiation-promotion protocols distinguishes DEHP and perhaps other peroxisomal proliferating chemicals from both classic liver carcinogens and promoters.
Occupational Hydrocarbon Exposure and Renal Histopathology
Authors: Pitha Jan V. , Hemstreet George P. , Asal Nabih R. , Petrone Robert L. , Trump Benjamin F. , Silva Fred G.
Published: September 2013

A blinded, retrospective study of histological sections from ten hydrocarbon-exposed and twenty unexposed nephrectomized renal cell carcinoma cases was conducted to evaluate the histopathologic features present in the apparently normal kidney parenchyma removed with the tumor. Tissue sections from each of the thirty cases were independently reviewed by three consulting pathologists and scored using well defined criteria. Occupational hydrocarbon exposure indices were developed by a team of industrial hygienists and applied to the detailed occupational history of each exposed case. A positive correlation was observed between age and the total renal pathology score ( rs = .40, p < .03). No correlation was found between indices of occupational hydrocarbon exposure and renal pathology scores among exposed cases. No significant differences in renal pathology scores were noted when exposed cases were matched to unexposed cases by age, sex, and race. These results are limited by the inclusion of only cases with historical hydrocarbon exposures. It is recommended that a follow-up study be conducted, utilizing sensitive quantitative methods, to define what, if any, cytopathologic renal effects occur in conjunction with current occupational exposures to hydrocarbons.
Methyl Tertiary Butyl Ether Inhalation in Rats: a Single Generation Reproduction Study
Authors: Biles Robert W. , Schroeder Raymond E. , Holdsworth Charles E.
Published: September 2013

Male rats exposed to target concentrations of methyl tertiary butyl ether (MtBE) at 300, 1300 and 3400 ppm for 6 hours/day, 5 days/ week for 12 weeks were mated to female rats exposed to the same concentrations for a 3-week period. Exposures continued through the mating period and the females continued exposures during ges tation and from days 5-21 lactation of the litters (F1a) (no expo sures days 0-4 lactation). A second litter (F1b) was produced under the same mating and post mating exposure regimen. No adverse effect of treatment was observed with the adult animals (Fo) throughout the in-life portion of the study. The only remarkable finding was an increased incidence of dilated renal pelves in the low- and high-dose females (Fo). All gonad weights, male accessory reproductive organ weights, organ-to-body weight ratios and reproductive organ histopathology were unremarkable upon com parison of treated animals with air sham controls. The mating indi ces and fertility indices in exposed animals for both mating intervals (F1a and F1b) were not significantly different from con trols. Pregnancy rates were comparable between treated and con trol females for the first litter interval (F 1a) but were slightly lower (not statistically significant) than control on the second litter inter val (F1b ). Treated animal mean gestation length and the mean number of pups at birth were not statistically different from con trols. The pup viability indices at birth were comparable for control and treated groups for the F1a generation, but the mid- and high- dose groups displayed a slight statistically significant decrease in the F1b generation; the decrease was not considered to be biologi cally significant and perhaps not treatment-related. Litter survival indices were comparable between control and treated groups for both litter intervals. Pups of mid- and high-dose females had slightly lower (not statistically significant) mean weights at days 14 and 21 of lactation but this was not considered treatment-related. The most frequent post-mortem observation for pups sacrificed at day 21 of lactation was dilated renal pelves. This did not appear to be related to treatment. It is concluded that MtBE inhalation in rats results in little adverse reproductive toxicity as shown in a two litter, one generation reproduction assay in rats.
Health Effects of the Alkylbenzenes. I. Toluene
Authors: Low Awrence K. , Meeks J. Ralph , Mackerer Carl R.
Published: September 2013

The alkylbenzenes, toluene being the most common example, represent a class of six-membered ring aromatic compounds that have a variety of alkyl groups attached. These chemicals are liquids with relatively low boiling points and are used primarily as solvents or as starting materials in the synthesis of other chemicals and drugs. They are also integral components of gasoline, distillate fuels and other petroleum products. These substituted aromatics are economically important in the chemical, petroleum, pharmaceutical, polymer, paint and dye industries. Alkylbenzenes such as toluene, xylene, ethylbenzene, styrene and cumene are toxicologically important since they are produced, used or disposed of in the largest quantities and therefore might pose significant and potential health risks to man and the environment. In general, the toxicity of alkylbenzenes has been found to be relatively low. Also, for the most part, human and environmental risks are low; however, there may be a few operations where the potential for high exposure could exist. These exposures are minimized by workplace controls or personal protective equipment. Furthermore, health risks for humans are minimized by guidelines for maximum allowable exposure concentrations which have been established for the workplace. This present paper reviews the toxicology and disposition of toluene in animals and humans.
Extracellular Ca2+-Dependent Elevation in Cytosolic Ca2+ Potentiates HgCl2-Induced Renal Proximal Tubular Cell Damage
Authors: Ambudkar Indu S. , Smith Mary W. , Phelps Patricia C. , Regec Annette L. , Trump Benjamin F.
Published: September 2013

While normal fluctuations of cytosolic Ca2 + ([ Ca2+] i) occur physiologically, the deregulation of cellular Ca2 + homeostasis leads to cellular injury. The contribution of [ Ca2+]i to the process of cellular damage was assessed in a model system where HgCl2 was used to induce plasma membrane damage in renal tubular cells. In the presence of 1.37 mM extracellular Ca2 +, HgCl2 (10-50 μM) induced a slow, dose-dependent, 4-6 fold increase in [ Ca2+]i (as measured by Quin 2) by 10 min of exposure, which could be abolished by prior incubation of the cells with dithiothreitol. Correlates of cellular injury, i.e., decrease in cell viability, change in cellular morphology, such as bleb formation, membrane distortion and mitochondrial swelling, were induced after HgCl2 addition. The rate and dose-responses of these changes were similar to that of [ Ca] i elevation. When cells were exposed to HgCl2 in the absence of added extracellular Ca2+ , there was no increase in [ Ca2+]i and both the rate and extent of cell damage were reduced. When Ca2 + was readded to the extracellular medium after HgCl2, there was a rapid elevation of [ Ca2 +] i, increased cell killing and bleb formation. The observed correlation between [ Ca2 +]i elevation, decreased cell viability and morphological aberrations in terms of (i) dose-dependency for HgCl2, (ii) requirement for high extracellular Ca2 +, and (iii) rate of change, suggests that HgCl2-induced renal cell damage involves the entry of Ca2 + from the extracellular milieu which potentiates the progression of cellular injury.
Case, the Computer-Automated Structure Evaluation System, as an Alternative To Extensive Animal Testing
Authors: Rosenkranz Herbert S. , Klopman Gilles
Published: September 2013

CASE, an artificial intelligence system with demonstrated ability to predict biological activity based on structural considerations, correctly predicts animal carcinogenicity. It can, therefore, play a pivotal role in classifying chemicals as carcinogens and prioritizing them for further testing. Additionally, CASE shows promise in the design of pharmacologically active agents by reducing the number of drugs that need to be synthesized and tested. For both of these applications, CASE provides a mechanism to conserve animal and other testing resources.
The Statistical Analysis of a Carcinogen Mixture Experiment. III. Carcinogens With Different Target Systems, Aflatoxin B1, N-Butyl-N-(4-Hydroxybutyl)Nitrosamine, Lead Acetate, and Thiouracil
Authors: Fears Thomas R. , Elashoff Robert M. , Schneiderman Marvin A.
Published: September 2013

This paper describes factorial experiments designed to determine whether two carcinogens that lead to cancers in different organ systems act synergistically to produce cancers in Fischer 344 rats. Four carcinogens, aflatoxin B1 (AFLA), N-butyl-n-(4-hydroxybutyl)nitrosamine (NBBN), lead acetate (LA), and thiouracil (THIO) were studied in pairwise combinations. Each of the six possible pairs were studied by means of a 4 X 4 factorial experiment, each agent being fed at zero and at three non-zero doses. Methods of analysis designed explicitly for this study were derived to study interaction. These methods were supplemented by standard statistical methods appropriate for single agent studies. Neither synergism nor antagonism was demonstrated in these combined exposure studies. Findings for male and female animals were consistent.
Indoor Air Contamination With Polychlorinated Dibenzo-p-Dioxins and Dibenzofurans
Authors: Mukerjee Debdas , Päpke Olaf , Karmaus Wilfried
Published: September 2013

Pentachlorophenol (PCP), used extensively for wood preservative purposes, contains trace amounts of polychlorinated dibenzo dioxins (PCDDs) and-dibenzofurans (PCDFs) as contaminants. Residues of these compounds are present on the surface and sub surface of the treated wood. These contaminants have the potential to wear (or migrate) away or volatilize from the wood surface and become entrained in ambient air or dust particles, and thus becom ing available for human contact. During the early sixties several day nursery facilities were built with PCP-treated wood in the northern part of West Germany. In this paper we describe the indoor air monitoring data in these kindergarten buildings and the associated possible long-term health risk. The indoor ambient air was found to be contaminated with highly toxic PCDDs/ PCDFs at pg/m3 levels. HxCDDs, HpCFs and OCDDs/OCDFs congeners were the major contaminants.
Problems in Assessing the Risks of Mixtures of Contaminants in Drinking Water
Authors: Vanderslice Robert R. , Orme Jennifer , Ohanian Edward V. , Sonich-Mullin Cynthia
Published: September 2013

In conducting risk assessments on drinking water contaminants, the U. S. Environmental Protection Agency (EPA) attempts to evaluate all available toxicity data to develop Health Advisory (HA) and Maximum Contaminant Level Goal (MCLG) values. The EPA often has grappled with the issues surrounding the toxic ity of chemical mixtures, including radioactive contaminants, nitrate/nitrite, and trihalomethanes (THMs). In evaluating the tox icity of chemical mixtures, the EPA's immediate concern is whether the individual HA values and MCLGs are protecting public health when multiple contaminants are present in drinking water. Poten tial toxic interactions between drinking water contaminants are dif ficult to predict because experimental studies are generally performed only at high doses relative to environmental levels. Although the contamination of drinking water involves mixtures of contaminants, drinking water regulations are generally based on an assessment of the risks of individual contaminants. This paper dis cusses three issues of major concern to the EPA: the synergistic effects of solvent mixtures, vehicle effects in laboratory studies, and setting standards for essential trace nutrients where the absorption and/ or toxicity are affected by an individual's nutritional status or other dietary components.
Development and Validation of in Vitro Induction Assays for Toxic Halogenated Aromatic Mixtures: A Review
Authors: Safe Stephen , Mason Grant , Sawyer Thomas , Zacharewski Tim , Harris Mark , Yao C. , Keys Barbara , Farrell Kathy , Holcomb Michael , Davis Deanne , Safe Lorna , Piskorska-Pliszczynska Jagoda , Leece Brian , Denomme Mary Anne , Hutzinger Otto , Thoma Heinz , Chittim Brock , Madge Jocelyn
Published: September 2013

Halogenated aromatic industrial compounds, typified by the polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) have been identified as residues in almost every component of the global ecosystem. Risk assessment of the complex mixtures of halogenated aromatics found in envi ronmental samples is complicated by analytical problems and the lack of toxicological information on individual compounds and mixtures. Research in our laboratory has focused on the develop ment and vadidation of the in vitro aryl hydrocarbon hydroxylase (AHH) induction assay in rat hepatoma H-4-II E cells in culture for quantitating individual toxic halogenated aryl hydrocarbons and their mixtures. For several PCB, PCDD, PCDF congeners, their mixed bromo/chloro analogs and reconstituted mixtures there was an excellent linear correlation between their -log ED50 values for AHH induction in rat hepatoma cells and their -log ED50 values for in vivo hepatic microsomal AHH induction, inhibi tion of body weight gain and thymic atrophy in the rat. It has also been shown for selected compounds that there was a good correla tion between their in vitro AHH induction potencies and their effects in guinea pigs (AHH induction, inhibition of body weight gain) and mice (immunotoxicity). This assay system has been uti lized to quantitate the "2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents "present in extracts from diverse sources including fly ash from a municipal incinerator and pyrolyzed brom inated flame retardants which contain a complex mixture of halo genated dibenzo-p-dioxins and dibenzofurans.
Scientific Trends in Risk Assessment Research
Authors: Anderson Elizabeth L.
Published: September 2013

The use of risk assessment approaches to evaluate the effects of toxic chemicals had its primary origin in 1976 when the U. S. Environmental Protection Agency (EPA) adopted the first federal guidelines to commit a major regulatory agency to risk assessment approaches for the evaluation of suspect carcinogens. The accom panying policy statement also adopted a risk management policy, which acknowledged that the agency would accept risk in making public health policy decisions; in essence, this represented a pri mary departure from the zero-risk goal that had dominated the first half of the environmental movement of the '70s. The approach adopted in 1976 was based on the experience of risk assessment approaches used for assessing low-dose-radiation effects on human health. To be certain that no public health risk be underestimated, particularly in light of the prior zero-risk goal, the practice of risk assessment for the first decade relied heavily on extremely protec tive assumptions in all aspects of the assessment process. For example, these assumptions included ranking the weight-of- evidence according to results in all related studies without regard for distinctions of tumor end point relevance to humans and the possibility that low-dose effects at environmental exposures might not be the same as high-dose effects. For low-dose-response charac terization, the practice has been to characterize a plausible upper bound on risk by the use of a low-dose linear non-threshold dose- response curve. Exposure assessment likewise relied on maximum plausible assumptions to characterize exposure. More recently, more attention is being paid to developing accurate scientific data bases that advance almost every aspect of the risk assessment pro cess in the direction of more accurate risk characterization.

This paper will discuss the recent trends in weight-of-evidence characterization, dose-response modeling, and exposure assessment and will compare the outcomes of these refined assessments to those evaluations that have relied on the earlier, conservative approaches. In essence, if the practices of the first decade for estab lishing plausible upper bounds on the risk were accurate, improved scientific data by and large should be expected to lower the overall theoretical risk. Indeed, this is the case when recent risk assessment research is applied but there are examples to the contrary. This paper represents a survey of recent trends and applications.
Evaluating Comparative Potencies: Developing Approaches To Risk Assessment of Chemical Mixtures
Authors: Schoeny Rita S. , Margosches Elizabeth
Published: September 2013

The U. S. EPA must provide guidance as to health risk assessment of mixtures from a variety of sources such as wastewaters, hazard ous waste sites and air particulates. One approach to risk assess ment of mixtures is to add up risk assessments for individual components identified as part of the mixture, after considering the potential for interaction among those components. This provides an index of hazard potential but not a quantitative estimate. When data on mixture components are incomplete, but these components are isomers or congeners of a well-studied chemical, another technique—use of toxic equivalency factors—can be applied. This approach has been proposed for estimating risk associated with chlorinated dioxins and dibenzofurans. A third approach, that of relative or comparative potency, is based on the assumption that for similar but not necessarily definable complex mixtures, a mea sure of relative potency based on data from in vitro tests can be correlated in a constant fashion with relative potency from an in vivo bioassay.

The degree of confidence in the appropriateness of a relative po tency method rests upon the way potency is measured and the validity of underlying assumptions (the degree to which these assumptions can be tested). One class of assumptions involves cho ice of the model or procedure for deriving the quantitative risk estimates. A second set of assumptions deals with mechanism of action, and whether such considerations add bias or, in fact, refine the relative potency judgment. The choice of short-term tests appropriate for use in establishing the potency relationships is also a factor to be considered. This paper presents examples of pro posed uses of relative potency in risk assessment and outlines some areas for further study.
Emerging Methodologies for Assessment of Complex Mixtures: Application of Bioassays in the Integrated Air Cancer Project
Authors: Lewtas Joellen
Published: September 2013

The assessment of complex mixtures of environmental pollutants requires new interdisciplinary strategies. Integration of bioassay methodologies into these strategies is an important tool that pro vides direct evidence of the toxicity of a mixture. Short-term genetic bioassays are now widely used in the cancer assessment of complex mixtures. New and emerging interdisciplinary methodolo gies for assessing complex mixtures using bioassays are illustrated by the U.S. EPA's Integrated Air Cancer Project (IACP). The goals of this project are to identify the major airborne carcinogens and their emission sources and to improve the methodology and data available for human exposure and risk assessment from air borne carcinogens. The research effort is focused primarily on characterizing the impact of complex mixtures of products of incomplete combustion, including gaseous, semi-volatile, and particle-bound organic species. Short-term genetic bioassays have been integrated into several analysis strategies, including environ mental biomonitoring; bioassay-directed fractionation/characteri zation; transformation studies; source apportionment; and exposure, dosimetry, and risk assessment.
II. In Vitro Effect of Copper on the Stromal Cells of Bone Marrow in Rats
Authors: Miszta Helena
Published: September 2013

The effect of copper inform of copper sulphate (CuSO4 × 5 H2O) was studied in the bone marrow cells of rats of Wistar strain in an in vitro culture. Evident differences between tissue cultures of the bone marrow cells were observed between the control and experimental groups. In the experimental group, the CFU-F colonies appeared as early as in 3rd day while in the control group in 5th day. Loosely arranged fibroblasts, macrophages and adipocytes also showed quantitative differences between groups. An increase in mean corpuscular hemoglobin (MCH) was also found in peripheral blood of experimental animals.
Developmental Toxicity of Hydroxylamine: An Example of a Maternally Mediated Effect
Authors: Desesso John M. , Goeringer Gerald C.
Published: September 2013

Hydroxylamine (HA) is an important reducing agent that is used in several industries. HA is a moderate irritant and a powerful inducer of methemoglobinemia. HA has been shown to react readily with DNA in vitro. Several chemical derivatives of HA are potent developmental toxicants, whereas HA has been reported to cause no develop-mentally toxic effects. Since HA and its developmentally toxic derivatives share the presence of a terminal hydroxylamine functional group (−NHOH), and since that functional group has been proposed to be the biologically active portion of the molecule, it was deemed appropriate to re-examine the possible developmental toxicity of HA. Subcutaneous or intravenous injection of pregnant rabbits with 50–650 mg HA·HCl/kg on gestational day 12 caused the death or sacrifice of all rabbits within 30 hours. All maternally injected rabbits exhibited severe cyanosis, presumably due to methemoglobinemia. Histological examination of embryos revealed alterations of the cardiovascular system at 5 hours, but an absence of cell death in limb buds. At 8 hours, all embryos were dead. These effects appear to be secondary to the observed cyanosis in the maternal animals. In order to circumvent the powerful methemoglobinemia-inducing properties of HA, in-tracoelomic injections of 25–200 μg HA·HCl in 5–40 μl of saline were made directly into the chorionic cavity of developing rabbit embryos, thereby bypassing the maternal system. Controls received similar volumes of saline. At doses of ≥ 75 μg, HA·HCl killed 91 percent of injected embryos; among survivors, all exhibited reduced birth weights and 215 exhibited malformations in the craniofacial region and sternum. At doses of 25–50 μg, HA·HCl caused increased resorptions compared with controls; however, surviving fetuses displayed neither malformations nor reduced birth weights. Histological analysis at 4 hours after injection revealed cellular debris in the limb buds; when the antioxidant propyl gallate was co-administered with HA, cellular debris was absent at 4 hours. It is concluded that although HA is a directly acting developmental toxicant if it reaches the embryo, the observed embryolethality seen after subcutaneous injection of pregnant animals is a consequence of the powerful maternal toxicity of HA.
Pulmonary Effects due to Subchronic Exposure to Oil Fog
Authors: Selgrade Maryjane K. , Hatch Gary E. , Grose Elaine C. , Stead Andrew G. , Miller Frederick J. , Graham Judith A. , Stevens Michael A. , Hardisty Jerry F.
Published: September 2013

Male and in some cases female rats were exposed to an oil fog generated by flash vaporization and subsequent condensation of lightweight lubricating oil. Exposures were for 3.5 h/d, 4d/wk for 13 wk. Males were exposed at concentrations of 1.5, 0.5, 0.2 or 0.0 mg/l (1500, 500, 200, and 0 mg/m3) and a particle size of approximately 1 μm (mass median aerodynamic diameter). A number of biologic end-points were assessed the day after the last exposure and, in some cases, after a 4 wk recovery period. Effects of 1.5 mg/l on male and female rats were compared. Diffuse accumulation of macrophages in the alveoli was observed in all oil fog exposed groups. The degree of severity was concentration dependent. Histopathologic changes were more prominent in males than in females and represented the most notable gender-related differences. Histologic effects observed one day and 4 wk post exposure were similar. Minimal histopathologic changes and minimal increase in lavage fluid protein were the only effects observed at the 0.2 mg/l exposure level. There was a significant increase in lavage fluid protein, percent lavagable polymorphonuclear leukocytes and lung wet and dry weight following exposure to both 0.5 and 1.5 mg/l. At the highest exposure concentration effects on lung weights were still evident 4 wk post exposure. Pulmonary function endpoints including total lung capacity, vital capacity, residual volume, diffusing capacity to CO, compliance, and end expiratory volume (EEV) were unaffected by oil fog exposure with the exception of EEV in males exposed at the 1.5 mg/l level. All of the changes observed following oil fog exposure were consistent with a mild inflammatory edema.
Growth and Development in the Rat during Sub-Chronic Exposure to Low Levels of Hydrogen Sulfide
Authors: Hayden Lawrence J. , Goeden Helen , Roth Sheldon H.
Published: September 2013

The effects of low levels of hydrogen sulfide (H2S) on mammalian growth and development are unknown although it has long been postulated that H2S can inhibit critical developmental functions through the cleavage of disulfide bonds and chelation of essential metal ions. Gravid rat dams exposed to H2S (≤75 PPM) from day 6 of gestation until day 21 postpartum (PP) demonstrated normal reproductive parameters until parturition. At parturition, however, delivery time was extended in a dose dependent manner with a maximum increase of 42% at 75 PPM. Maternal liver cholesterol content was elevated significantly on day 21 postpartum following exposure to 75 PPM H2S each day for 6 weeks. Pups which were exposed in utero and neonatally to day 21 postpartum developed with a subtle decrease in time of ear detachment and hair development and with no other observed change in growth and development throughday 21 postpartum.
Dangerous and Cancer-Causing Properties of Products and Chemicals in the Oil Refining and Petrochemical Industry - Part II: Carcinogenicity, Mutagenicity, and Developmental Toxicity of 1,3-Butadiene
Authors: Mehlman M.A. , Legator M.S.
Published: September 2013

1,3-butadiene (BD) is present in synthetic rubber and motor fuels (gasoline). BD is shown to cause lymphocytic lymphomas, heart hemangiosarcomas, lung alveolar bronchiolar cancers, forestomach-squamous cell cancers, harderian gland neoplasms, preputial gland adenoma or carcinoma, liver-hepatocellular cancers, mammary gland acinar cell carcinomas, ovary-glanulosa cell carcinoma, brain cancers, pancreas adenoma and carcinoma, testis-Leydig cell tumors, thyroid follicular adenoma and carcinoma, and zymbal gland carcinoma in rodents and to date no exposure level has been established at which this chemical does not cause cancers.

In humans BD causes increase in lymphomas, leukemias, and other cancers of hematopoietic systems and organs. BD is also a potent alkylating agent, directly toxic to developing embryos and damages progeny after parental exposure.
An Integrated Exposure/ Pharmacokinetic Based Approach to the Assessment of Complex Exposures
Authors: Derosa C.T. , Choudhury H. , Peirano W.B.
Published: September 2013

A problem in evaluating the hazard represented by an environ mental toxicant is that exposures can occur via multiple media such as water, land, and air. Lead is one of the toxicants of con cern that has been associated with adverse effects on heme me tabolism, serum vitamin D levels, and the mental and physical development of infants and children exposed at very low envi ronmental levels. Effects of lead on development are particularly disturbing in that the consequences of early delays or deficits in physical or mental development may have long-term conse quences over the lifetime of affected individuals.

Experimental and epidemiologic studies have indicated that blood lead levels in the range of 10-15 μ g/ dl , or possibly lower, are likely to produce subclinical toxicity. Since a discernible threshold has not been demonstrated, it is prudent to preclude development of a Reference Dose (RfD) for lead. As an alter nate, the U. S. Environmental Protection Agency (U. S. EPA) has developed the uptake/biokinetic lead model that provides a means for evaluating the relative contribution of various media to establishing blood lead levels in children. This approach will allow for the identification of site- and situation-specific abate ment strategies based on projected blood lead levels in vulnera ble human populations exposed to lead in air, diet, water, soil/ dust, and paint; thus making it possible to evaluate regulatory decisions concerning each medium on blood levels and potential health effects.
Effects of Methanol Vapors on Testosterone Production and Testis Morphology in Rats
Authors: Lee E. , Brady A.N. , Brabec M.J. , Fabel T.
Published: September 2013

Potential toxic effects of methanol vapors on testicular produc tion of testosterone and the morphology of testes were investi gated using normal or methanol-sensitive folate-reduced rats. Methanol inhalation at the level of the current permissible expo sure limit, 200 ppm, for up to six weeks (8 hours/day, 5 days/ week), did not reduce serum testosterone levels in normal rats. Testes isolated from methanol-exposed (200 ppm) rats had the same capability as those from air-exposed rats in synthesizing testosterone whether testes were incubated in the absence or pres ence of hCG. The testes-to-body weight ratio of rats exposed up to 800 ppm methanol for up to 13 weeks (20 hours/day, 7 days/ week) were not different from those of the air-exposed rats. Fur thermore, methanol had no adverse effect on testicular morphol ogy at the end of the 13 week exposure period at 800 ppm in either normal rats or folate-reduced methanol-sensitive rats when they were 10 months old at the time of examination. Thus, these data indicate that low level methanol may not cause an inhibi tory effect on testosterone synthesis contrary to previous litera ture reports. However, a greater incidence of testicular degeneration was noticed in the 18 month old folate-reduced rats exposed to 800 ppm for 13 weeks (20 hours/day, 7 days/week), suggesting that methanol may have a potential to accelerate the age-related degeneration of the testes.
Lung Burden of a Glass Fiber By Inhalation
Authors: Tanaka Isamu , Akiyama Takashi , Kido Masamitsu
Published: September 2013

Pulmonary deposition and clearance of deposited particles from lungs are very important factors in order to induce pneumoconioses.

In this paper, five Wistar male rats were exposed to glass fiber particles( mass median aerodynamic diameter(MMAD), 2.8 μm) for 6 hrs/day, 5 days/week for 4 weeks. The average expo sure concentration was controlled by a continuous fluidized bed with a screw feeder and an overflow pipe at 0.79 mg/m during the exposure period. The fibrous particles concentra tions in the exposure chamber were monitored by a light scat tering method and showed to be constant during the exposure.

The rats were sacrificed at 24 hours after the termina tion of the exposure and then the wet lung weight and the silica concentration in the lungs were measured. The lungs were treated for low temperature ashing (ca. 150 °C) by a plasma asher. After ashing, these samples were melted with sodium carbonate in platinum pot for the measurement of the silica content by the absorption spectrophptometry.

The maximum content of SiO2 was 45 μg in the exposed rats and 20 μg in the control, The deposited amount of SiO2 by the exposure to glass fiber was 25 μg. The apparent deposition fraction defined as the deposited amount in the lungs to the amount of the inhaled glass fiber during the exposure was 6.8 %. There was no significant difference of the apparent deposi tion fraction at same MMAD between glass fiber in this study and non-fibrous particles.
Evaluation of Heat Sterilization of Commercial Rat Diets for Use in Fda Toxicological Studies
Authors: Collins Thomas F.X. , Hinton Dennis M. , Welsh John J. , Black Thomas N.
Published: September 2013

Certified commercial rat diets, control and fortified, in the form of pellets and meal, were evaluated in a simulated subchronic rat feeding study. The diets were analyzed before and after autoclaving to determine nutrient integrity and loss, as well as the efficiency of autoclaving for removal of microbiological contaminants. Sterilization reduced the level of heat-labile vitamins, but protein level was minimally reduced. Sterilization eliminated most of the bacterial contaminants and virtually all the mold and yeast colonies. Male and female Osborne-Mendel rats (3-4 wk old) were fed control or sterilized diet for 6 wk. Both males and females consumed more pelleted chow than meal chow. This apparent difference in consumption may be due to wastage of pellets, because there were no differences in male or female growth during the 6-wk study. At necropsy, no gross pathology was noted, and organ weights did not differ significantly among the groups for either sex. Testicular weights were also similar among the groups. Blood serum proteins were analyzed by electrophoresis to screen for possible effects on various target organs. Gamma globulin levels for female rats fed sterilized meal were significantly reduced compared to levels for rats fed the control diet. These results suggest that either nutritional factors or heat inactivation of the microbes affects basal levels of humoral immunity, possibly by reduction of gut-mediated immune responses.
Tissue Distribution of Monochloroacetic Acid and Its Binding To Albumin in Rats
Authors: Kaphalia Bhupendra S. , Bhat Hari K. , Khan M. Firoze , Ansari G.A.S.
Published: September 2013

Distribution of monochloroacetic acid (CA) was studied in rats given a single oral dose of 0.1 mmole/kg body weight [ 1-14 C] CA, by gavage. The animals were sacrificed at 4, 8, 12, 24 and 48 hr following the treatment. The distribution of14 C-label, determined in different tissues, suggests that CA is rapidly absorbed and eliminated from the body. The elimination phase appears to be fast for intestine and kidney as compared to other tissues. Maximum radioactivity was detected in intestine and kidney at 4 and 8 hr following the treatment which was followed by liver, spleen, testes, lung, brain and heart in a decreasing order. A group of rats treated with a single oral dose of 1 mmole/kg [ 1-14 C] CA, by gavage, was also sacrificed at 24 hr following the exposure to study the effect of a higher dose on distribution of [ 1-14 C] CA. The distribution of 14 C-label at both dose levels indicates that toxicokinetic properties of CA are dose-dependent. Another group of rats administered 1 mmole/kg [ 1-14 C] CA daily for three days was also sacrificed at 24 hr following the last dose to evaluate the bioaccumulating properties of CA and/or its metabolites in the tissues. As compared to the number of doses given, the accumilation of14 C-label was not as large as expected.14 C-Label determined in the dialyzed plasma, suggests an in vivo binding of14 C-label to plasma proteins where albumin accounted for about 65% as determined by affinity chromatography. Isolation and identification of the adducts of amino acids will help in understanding the mechanism of CA toxicity and development of a suitable biomarker of CA exposure.
Effects on Neurobehavioral Performance of Chronic Exposure to Chemically Contaminated Well Water
Authors: Kilbum Kaye H. , Warshaw Raphael H.
Published: September 2013

Occupational exposure lo trichloroethylene (TCE) and other solvents impairs neurobehavioral performance. Use of well water contaminated with TCE and solvents has been associated with excessive symptoms, cancers, birth defects and impaired blink reflex. We extended these observations by measuring the neurophysiological (NPH) and neuropsychological (NPS) status of subjects who used water contaminated with 6 to 500 ppb of TCE for 1 to 25 years.

The 170 well-water exposed subjects who resided in southwest Tucson, Arizona overlying the Santa Cruz River aquifer, were compared to 68 referent subjects for NPH and NPS tests. Also, 113 histology technicians (HT) were referents for blink reflex latency only. Affective status was assayed by a Profile of Mood States (POMS).

Exposed subjects were statistically significantly impaired when compared to referents for NPH tests. These impairments included sway speed with eyes open and closed, blink reflex latency (R-1), eye closure speed, and two choice visual reaction time. NPS status was statistically significant impaired for Culture Fair (intelligence) scores, recall of stories, visual recall, digit span, block design, recognition of fingertip numbers, grooved pegboard and Trail making A and B. POMS scores were elevated.

Prolonged residential exposure to well-water containing TCE at lower levels than occupational exposures, but without time away from exposure for metabolism and excretion of toxins, was associated with neurobehavioral impairment.
Primary Aromatic Amines from Side-Stream Cigarette Smoke are Common Contaminants of Indoor Air
Authors: Luceri Francesca , Pieraccini Giuseppe , Moneti Gloriano , Dolara Piero
Published: September 2013

A very sensitive mass-spectrometry method has been developed for the analysis of aromatic amines in tobacco smoke and in indoor air. Cigarettes were smoked with a smoking machine; the anwies from the smoke were trapped in a 5% HCl water solution containing internal standards and detected by gas chromatography/mass spectrometry in the selected-ion-monitoring (SIM) mode. The amines measured were the following: aniline. 2-toluidine, 3-toluidine, 4-toluidine, 2-ethylaniline, 3-ethylaniline, 4-ethylaniline, 2,3-dimethylaniline, 2,4-dimethylaniline, 2,5-dimethylaniline, 2,6-dimethylaniline, 1-naphthylamine, 2-naphthylamine, 2-methyl-1-naphthylamine, 2-aminobiphenyl,3-aminobiphenyl and 4-aminobiphenyl.

We analyzed nine brands of cigarettes sold commercially in Italy (Gauloise, Nazionali, Marlboro, Camel, MS, MS mild and MS lights), with and without filter.

Main-stream smoke contained a lower amount of aromatic amines than side-stream smoke: the total level of these amines in main-stream smoke ranged from 200 to 1300 nglcigarette, whereas the level of aromatic amines in side-stream smoke varied from 20,000 to 30,000 nglcigarette. The smoke of black-tobacco cigarettes had higher levels of aromatic amines compared to light-tobacco cigarettes and the filters significantly reduced aromatic amines in main-stream smoke.

We also determined the levels of aromatic amines in ambient air, offices and houses. Some aromatic amines (aniline and toluidine) were detected in ambient air, as well as in rooms of non-smokers. Most measurements showed a considerable contamination of aromatic amines derived from side-stream smoke, which was detected also in parts of the buildings in which smoking was not allowed.
Characterization of Highly Polar Dna Adducts Derived from Dibenz[A,H]Anthracene (DBA), 3,4-Dihydroxy-3,4-Dihydro-DBA, and 3,4,10,11-Tetrahydroxy-3,4,10,11-Tetrahydro-DBA
Authors: Fuchs Juergen , Mlcoch Jiri , Oesch Franz , Platt Karl Ludwig
Published: September 2013

Two highly polar DNA adducts were found after metabolic activation of 3,4,10,11-tetrahydroxy-3,4,10,11-tetrahydrodibenz[ a,h]anthracene(DBA-3,4;10, 11-bisdiol) by liver microsomes isolated from male Sprague-Dawley rats pretreated with Aroclor 1254 in presence of calf thymus DNA. These DNA adducts could be assigned to the metabolites of dibenz[ a,h]anthracene (DBA), of 3R,4R,10R,11R-tetrahydroxy-3,4,10,11-tetrahydro-DBA and of 3R,4R,10S,US-tetrahydroxy-3,4,10,11-tetrahydro-DBA. DNA adducts derived from metabolites of 3S,4S,10S,11S-tetrahydroxy-3,4,10,11-tetrahydro-DBA were not found.

These highly polar adducts also could be detected by reversed phase HPLC after incubation of dibenz[ a,h]anthracene, 3R,4R-dihydroxy-3,4-dihydro-DBA ((-)-DBA-3,4-diol) and 3S,4S- dihydroxy-3,4-dihydro-DBA ((+)-DBA-3,4-diol) with DNA in presence of the activating system. After incubation of 14C labelled DBA DNA adducts derived from DBA-3,4;10,11-bisdiol were found in a fraction of 38% and bay region 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydro-DBA-DNA adducts at a level of 25%. DBA-3,4; 10,11-bisdiol exhibited a higher DNA binding yield (38 × 12 pmollmg DNA) than (-)-DBA-3,4-diol (23 × 6 pmol/mg DNA), the most mutagenic 3,4-diol enantiomer. For (+)-DBA-3,4-diol the highly polar DNA adducts derived from DBA-3,4;10,11-bisdiol were by far the most predotmnant adducts in vitro.
Age-Dependent Neurotoxicity in Rats Chronically Exposed to Low Level Lead Ingestion: Phospholipid Metabolism in Synaptosomes and Microvessels
Authors: Singh Ashok K.
Published: September 2013

The uptake of [ 3H]Ch and [3H]MI by synaptosomes or microvessels, the concentration of membrane phospholipids, and the incorporation of [ 3H]Ch or [3H]MI into the respective phospholipids in synaptosomes or microvessels, were studied in samples obtained from the brain of control rats and rats exposed to a low-level lead ingestion starting prenatally, neonatally or at an adult age. The Vmax values for the uptake of [3H]Ch by control-neonatal and control-adult samples were significantly different. However, there was no significant difference in the Vmax values for the uptake of [3H]MI by control-neonatal and control- adult samples. The same was true for the Km values for the uptake of [3H]Ch or [ 3H]MI. Chronic exposure of embryonic and neonatal rats to a low-level lead ingestion inhibited the rate of uptake of [3H]Ch and [3H]MI by the brain synaptosomes or microvessels, reduced the concentrations of Ch and MI phospholipids in membranes of these tissues, and did not effect the incorporation of [3H]Ch and [3H]MI into the respective membrane phospholipids. In adult rats, these changes were not observed following chronic exposure. These observations suggest that Ch and MI transport mechanisms in the brain of embryonic and neonatal rats are sensitive to chronic low-level lead ingestion but Ch and MI transport mechanisms in the brain of adult rats are not. A lead-induced decrease in the availability of Ch and MI in the brain may be responsible for the observed decrease in the concentrations of phospholipids.
Nephrotoxic Effects of Thermal Decomposition Mixtures of Type C Hydraulic Fluids
Authors: Van Dam Jozef J. , Verbeken Erik K. , Daenens Paul J. A.
Published: September 2013

A survey was conducted to check the toxicological impact of ethylene glycol present in a thermal decomposition mixture of type C hydraulic fluid on laboratory animals submitted to an inhalation test. The target organs, i.e. kidneys, of exposed rats were evaluated histologically and oxalic acid—the ethylene glycol metabolite thought to cause renal failure—was quantified in urine samples. The results show that the low ethylene glycol concentrations present in the inhalation chamber produce only a temporarily increased oxalic acid excretion, at levels that are not significant. These findings are supported by the histological evaluation of the kidneys showing no calcium oxalate deposits or other abnormalities.
Effect of Subacute Toluene Administration on the Enkephalinergic Neuromodulatory System in Rats and Protective Action of Ganglioside Treatments
Authors: De Gandarias Juan M. , Echevarria Enrique , Serrano Roberto , Irazusta Jon , Casis Luis
Published: September 2013

Gangliosides perform protective functions in the central nervous system. This paper describes a study of the effect of ganglioside administration on toluene neurotoxicity. Rat brain met-enkephalin immunostaining in the central amygdaloid nuclei showed changes in rats treated simultaneously with gangliosides and toluene with respect to rats treated with toluene alone. It is suggested that gangliosides prevent toluene neurotoxicity at this level, leading to hypothetical neurobehavioral changes.