Biomedical subjects

D R Mattie

Publications and source records attributed to D R Mattie.

At least 19 recordsLinked to original sources

PubMed2003

Sensitive high-performance liquid chromatography method for the determination of low levels of perchlorate in biological samples.

A rapid and sensitive high-performance liquid chromatography (HPLC) method was developed to detect perchlorate in tissues of male and female rats, both pregnant and lactating (including milk) after administration of perchlorate. Supernatants of ethanol precipitated rat fluids and tissues were evaporated to dryness under nitrogen and reconstituted in deionized water. Reconstituted samples were injected into HPLC system coupled with conductivity detection. Isocratic separation of perchlorate was achieved using an anion-exchange column with sodium hydroxide as mobile phase and a conductivity detector. In this method, perchlorate showed a linear response range from 5 to 100 ng/ml. The lower detection limits for perchlorate in fluids and tissues of rats were 3-6 ng/ml and 0.007-0.7 mg/kg, respectively. The described method has the unique advantage over the existing methods of determining low traces of perchlorate in different biological matrices without complex sample preparation.

Animals↗

PubMed2000

A 90-day drinking water toxicity study in rats of the environmental contaminant ammonium perchlorate.

Perchlorate (ClO(4)(-)), the dissociated anion of perchlorate salts such as ammonium, potassium, and sodium perchlorate, has been recently recognized as a persistent and pervasive contaminant of drinking water supplies in a number of metropolitan areas. Perchlorate is of concern because of uncertainties in the toxicological database available to address the potential human health effects of low-level exposure. The purpose of this study was to evaluate the subchronic toxicity of perchlorate when administered to Sprague-Dawley rats as ammonium perchlorate (AP) for 14 or 90 days. The study consisted of an untreated control group and five treatment groups that received continuous exposure to AP via the drinking water at dosage levels of 0.01, 0.05, 0.2, 1.0, and 10.0 mg/kg/day. The study design included a nontreatment recovery period of 30 days to evaluate the reversibility of any AP-induced effects at the 0.05, 1.0, and 10.0 mg/kg/day levels. The study also investigated the potential effects of AP on male sperm parameters, female estrous cyclicity, bone marrow micronucleus formation, and serum hormone levels, i.e., triiodothyronine (T(3)), thyroxine (T(4)), and thyroid stimulating hormone (TSH). No toxicologically meaningful differences were observed between the control and AP-treated groups with respect to survival, clinical observations, body weights, food consumption, water consumption, ophthalmology, hematology, clinical chemistry, estrous cycling, sperm parameters, or bone marrow micronucleus formation. A target organ effect was produced by AP in the thyroids of male and female rats at the 10 mg/kg/day level after 14 and 90 days of exposure. The effect was characterized by significantly increased thyroid weights and thyroid histopathology consisting primarily of follicular cell hypertrophy with microfollicle formation and colloid depletion. These changes were reversible after a nontreatment recovery period of 30 days. Statistically significant changes in TSH and thyroid hormones were observed at all AP dosage levels tested; however, no thyroid organ weight or histopathological effects were observed at AP dosage levels < or = 1.0 mg/kg/day. In the absence of thyroid organ weight and histopathological effects, the toxicological significance of TSH and thyroid hormone changes at AP dosage levels < or = 1.0 mg/kg/day remains to be determined.

Animals↗

PubMed1999

Dose-response hapatotoxicity of the peroxisome proliferator, perfluorodecanoic acid and the relationship to phospholipid metabolism in rats.

Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator that causes hepatotoxicity but lacks tumor-promoting activity in rats. We previously showed that a single dose of PFDA at 50 mg/kg (approximately LD50) causes an elevation in liver phosphocholine (PCho) and other effects related to phospholipid metabolism. In this study, we examined metabolic effects in the dose range 2-50 mg/kg in rats. At doses < or =20 mg/kg, PFDA is significantly less hepatotoxic than the LD50 as manifested by electron microscopy and measurements of daily food consumption and body weight. At 50 mg/kg rat serum tumor necrosis factor (TNF)-alpha concentration was increased 8-fold, while at 15 mg/kg there was no apparent increase in this cytokine. This lower dose, however, induces metabolic effects similar to those seen at the LD50. Liver fatty acyl-CoA oxidase activity showed a dose-dependent increase from 5-25 mg/kg PFDA. Treatments at 15 and 50 mg/kg caused a significant increase in liver phosphatidylcholine (28 and 66%) and phosphatidylethanolamine (31 and 74%). Both doses caused a significant increase in liver PCho but did not affect liver ATP levels, as manifested in 31P nuclear magnetic resonance (NMR) spectra from rat livers in vivo. These data suggest that the increase in liver [PCho] observed following PFDA exposure in rats represents a specific metabolic response, rather than a broad-range hepatotoxic effect.

Acyl-CoA Oxidase↗

PubMed1997

Inflammatory damage to skin by prolonged contact with 1,2-dichlorobenzene and chloropentafluorobenzene.

Skin samples from Fischer-344 rats and Hartley guinea pigs exposed dermally to 1,2-dichlorobenzene (DCB) and chloropentafluorobenzene (CPFB) for up to 4 h were examined for chemical-induced damage. Samples were stained with hematoxylin and eosin and scored for polymorphonuclear cell (PMN) margination, dermal inflammation, and epidermal necrosis by light microscopy. Ultrastructural evaluation of samples fixed with 2% glutaraldehyde and postfixed with 1% osmium tetroxide was used to visualize margination of PMNs. Guinea pigs exhibited postexposure inflammatory changes following an exposure of about an hour-and-a-half shorter duration than rats. DCB-induced inflammation and PMN margination occurred following an exposure about a half hour shorter in both species compared to CPFB. In contrast, epidermal necrosis was more severe with CPFB than with DCB. These changes may account for decreases in chemical penetration rates which have been observed in previous studies with DCB and CPFB in rats and guinea pigs.

Animals↗

PubMed1995

The metabolism of n-nonane in male Fischer 344 rats.

The urinary metabolites of n-nonane in male Fischer 344 rats, after administering the hydrocarbon by gavage, included gamma-valerolactone, delta-hexanolactone, 2,5-hexanedione, delta-heptanolactone, 1-heptanol, 2-nonanol, 3-nonanol, 4-nonanol, 4-nonanone and 5-methyl-2-(3-oxobutyl)furan. Metabolism strongly favored the formation of monoalcohols and lactones, which are the products of appropriately substituted hydroxy carboxylic acids. The metabolites were identified using gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS). High pressure liquid chromatography (HPLC) permitted the detection of the dicarboxylic acids malonic acid and glutaric acid in the n-nonane dosed rat urines.

Alcohols↗

PubMed1995

Program development in military toxicology laboratories.

Military toxicology evolved from needs identified during the World Wars. The Army, Navy and Air Force developed toxicological capabilities in response to their respective operational needs. These 3 previously separate military toxicology efforts have been integrated into Tri-Service Toxicology in response to the continually changing and growing operational needs of the military. The continual process of program development must be initiated in order for Tri-Service Toxicology to improve, grow and better serve its customers. Program development entails developing and maintaining good customer relationships and cooperative relationships with other governmental agencies, industry and academia. The benefits of identifying and obtaining customers and collaborators will substantially outweigh the costs incurred by committing to the implementation of program development within Tri-Service Toxicology.

Humans↗

PubMed1994

Determination of skin:air partition coefficients for volatile chemicals: experimental method and applications.

The partition coefficient (PC) of a chemical in skin is an indicator of the capacity for a chemical in the skin and may reflect the rate at which a chemical penetrates the skin and enters into systemic circulation. In this study we present a simple method to measure the skin:air PC for volatile organic chemicals. Important considerations in the development of this method for a skin:air PC were the effect of size and shape of the skin sample, initial chemical concentration, and time to equilibrium in the skin. Clipped, whole-thickness skin was obtained from the dorsal surface of 8- to 16-week-old male F-344 rats. After removal of the hypodermis, skin was cut into strips and placed on the side of a glass vial. An organic chemical vapor was introduced into a sealed sample vial (initial concentration before equilibration was 203 ppm) and a corresponding reference vial, which were equilibrated at 32 degrees C. Headspace concentrations at equilibrium were used to determine a skin:air PC value. After developing the technique using dibromomethane, a skin:air PC value was determined for perchloroethylene, trichloroethylene, benzene, hexane, toluene, m-xylene, styrene, methyl chloroform, methylene chloride, carbon tetrachloride, halothane, and isoflurane. The skin:air PC values correlated with previously determined vapor permeability constants but correlated poorly with octanol/water PC values. This method provides a screening technique for predicting skin penetration of volatile chemicals.

Air↗

PubMed1994

Significance of the dermal route of exposure to risk assessment.

The skin is a route of exposure that needs to be considered when conducting a risk assessment. It is necessary to identify the potential for dermal penetration by a chemical as well as to determine the overall importance of the dermal route of exposure as compared with inhalation or oral routes of exposure. The physical state of the chemical, vapor or liquid, the concentration, neat or dilute, and the vehicle, lipid or aqueous, is also important. Dermal risk is related to the product of the amounts of penetration and toxicity. Toxicity involves local effects on the skin itself and the potential for systemic effects. Dermal penetration is described in large part by the permeability constant. When permeability constants are not known, partition coefficients can be used to estimate a chemical's potential to permeate the skin. With these concepts in mind, a tiered approach is proposed for dermal risk assessment. A key first step is the determination of a skin-to-air or skin-to-medium partition coefficient to estimate a potential for dermal absorption. Building a physiologically-based pharmacokinetic (PBPK) model is another step in the tiered approach and is useful prior to classical in vivo toxicity tests. A PBPK model can be used to determine a permeability constant for a chemical as well as to show the distribution of the chemical systemically. A detailed understanding of species differences in the structure and function of the skin and how they relate to differences in penetration rates is necessary in order to extrapolate animal data from PBPK models to the human. A study is in progress to examine anatomical differences for four species.

Animals↗

PubMed1993

The toxicologic and oncogenic potential of JP-4 jet fuel vapors in rats and mice: 12-month intermittent inhalation exposures.

Three-hundred Fischer 344 rats and 300 C57BL/6 mice of each sex were divided into three treatment groups and exposed intermittently (6 hr/day, 5 days/week) to JP-4 jet fuel vapors at concentrations of 0, 1000, and 5000 mg/m3 for 12 months. At exposure termination, 10% of the animals were killed and those remaining were held for a 12-month postexposure tumorigenesis observation period. Pathologic findings in male rats revealed treatment-related renal toxicity and neoplasia consistent with the male rat unique alpha 2 mu-globulin nephropathy syndrome. Distinct JP-4-induced respiratory toxicity was not observed, and pulmonary neoplasms were not significantly increased in any treatment group. Benign hepatocellular adenomas were slightly increased in high-dose female mice, but the trend was reversed in male mice. Other pathologic findings were regarded as equivocal or compatible with expected biologic variation. The study did not demonstrate target organ toxicity or carcinogenesis which could be extrapolated to other species.

Administration, Inhalation↗

PubMed1991

Effects of short-term oral dosing of polychlorotrifluoroethylene (polyCTFE) on the rhesus monkey.

Polychlorotrifluoroethylene (polyCTFE--primarily oligomers with 3-4 monomer units), a non-flammable hydraulic fluid for aircraft, was given daily for 15 days by oral gavage to four Rhesus monkeys at a concentration of 0.725 g kg-1. The administered dose was at a level that had caused toxicity in rats. Steady-state blood and liver concentrations reached were the same in both species. In monkeys, polyCTFE did not cause the electrolyte, serum protein, liver enzyme and anemic disturbances previously seen in rats. Liver sections taken at 15 days, analyzed for palmitoyl Co-A beta-oxidation rates or by electron microscopy, showed no significant indication of peroxisomal proliferation. An increased blood urea nitrogen (BUN) at 15 days was the only clinical pathological abnormality seen in both monkeys and rats. Previously unobserved effects were increased triglycerides and glycogen depletion.

Administration, Oral↗

PubMed1991

Comparative hepatotoxicity of two polychlorotrifluoroethylenes (3.1 oils) and two chlorotrifluoroethylene (CTFE) oligomers in male Fischer 344 rats.

Polychlorotrifluoroethylene (3.1 oil) is a nonflammable hydraulic fluid composed of chlorotrifluoroethylene (CTFE) oligomers of different carbon chain lengths (C5 to C9), primarily six (trimer) and eight (tetramer) carbons. Four test groups of Fischer 344 rats (16 rats/group) were orally gavaged daily over a 2-week period at doses of 1.25 g/kg with 3.1 oil containing a 55:45 ratio of trimer and tetramer (3.1 oil-C6:C8), 3.1 oil composed of 95% trimer (3.1 oil-C6), pure tetramer, and pure trimer. Four rats per treatment group were terminated after 1, 3, 7, and 14 doses. Rats dosed with either 3.1 oil-C6:C8 or pure tetramer demonstrated significant weight losses, increased liver weights, increased rates of liver fatty acid beta-oxidation, pronounced hepatomegaly and altered hepatocellular architecture, and elevated serum liver-associated enzymes. Rats dosed with either 3.1 oil-C6 or only pure trimer demonstrated significant increase in liver weight and moderate liver histopathologic changes. Compositional analyses of the ratio percentage of trimer to tetramer present in 3.1 oil-C6:C8 (55:45) were found to be altered when measured in the liver (32:68). Differential CTFE oligomer toxicity was indicated by effects on liver, body weight, and peroxisomal beta-oxidation and may allow for less toxic formulations of 3.1 oil to be generated by reducing or eliminating the tetramer component.

Animals↗

PubMed1991

Dermal absorption of neat and aqueous volatile organic chemicals in the Fischer 344 rat.

Quantification of dermal absorption of volatile organic chemicals (VOCs) from aqueous solutions is required to understand the potential health hazards resulting from skin exposure to these chemicals in contaminated water. Male Fischer 344 rats were dermally exposed (3.1-cm2 dorsal skin) to neat, one-third saturated, two-thirds saturated, or saturated aqueous solutions of 14 VOCs for 24 hr. Blood samples were obtained via indwelling jugular catheters during exposure (0, 0.5, 1, 2, 4, 8, 12, and 24 hr), and analyzed for the VOCs by gas chromatography using headspace analysis. Absorption of the neat VOCs in this series of chemicals decreased as water solubility decreased. Peak blood levels of VOCs attained during exposure for 24 hr to neat chemicals were: 1,2-dichloroethane (135.1 micrograms/ml), bromochloromethane (113.3 micrograms/ml), chloroform (51.0 micrograms/ml), benzene (24.2 micrograms/ml), tetrachloroethylene (21.1 micrograms/ml), dibromomethane (18.2 micrograms/ml), trichloroethylene (11.6 micrograms/ml), toluene (9.5 micrograms/ml), xylene (8.8 micrograms/ml), hexane (8.0 micrograms/ml), ethylbenzene (5.6 micrograms/ml), styrene (5.3 micrograms/ml), carbon tetrachloride (5.0 micrograms/ml), and 1,1,1-trichloroethane (3.4 micrograms/ml). Blood levels of 1,2-dichloroethane and benzene continued to increase during the 24-hr exposure to neat chemical, while blood levels of the other neat VOCs peaked within 4 hr and then either decreased or remained about the same for the duration of the exposure. Absorption of VOCs from one-third, two-thirds, or saturated aqueous solutions was rapid, and resulted in depletion of the chemical from the solution although only a small amount of water was absorbed. Blood levels of each VOC were directly related to the exposure concentrations. The rapid appearance of VOCs in the blood from aqueous solutions demonstrates that detectable amounts of VOCs were absorbed during exposure of only about 1% of the skin surface area of the rat.

Animals↗

PubMed1991

A 90-day continuous vapor inhalation toxicity study of JP-8 jet fuel followed by 20 or 21 months of recovery in Fischer 344 rats and C57BL/6 mice.

The kerosene-type jet fuel, JP-8, consists of a complex mixture of aliphatic and aromatic hydrocarbons. Because of the utility of JP-8, studies have been conducted to identify the potential long-term consequence of occupational inhalation exposure. Fischer 344 rats and C57BL/6 mice of both sexes were exposed to JP-8 vapors at 0, 500, and 1,000 mg/m3 on a continuous basis for 90 days, then followed by recovery until approximately 24 months of age. Occurrence of necrotizing dermatitis associated with fighting resulted in an increase in mortality in mice (male greater than female) during the 2 week to 9 month post-exposure recovery period. The male rat kidney developed a reversible ultrastructural increase in size and propensity for crystalloid changes of phagolysosomal proteinic reabsorption droplets in the proximal convoluted tubular epithelium. A specific triad of persisting light microscopic renal lesions occurred but functional change was limited to a decrease in urine concentration compared to controls that persisted throughout the recovery period. The response is comparable to the chronic effect of lifetime exposure of the male rat to unleaded gasoline, d-limonene, and p-dichlorobenzene, except for the absence of tubular tumorigenesis. The active toxicologic response presumably must occur over a greater proportion of the male rat's life span for the tumor component of this male rat hydrocarbon nephropathy syndrome. The predictiveness for humans must be questioned, since the pathologic response to JP-8 involved only one tissue in one sex of one species, and since the male rat response appears to be linked to an inherent renal protein peculiarity.

Administration, Inhalation↗

PubMed1990

Lack of detectable metabolism for solubilized 2,3,4-trimethylpentane by rat kidney proximal tubules.

Primary proximal tubule suspension cultures exposed to solubilized 2,3,4-trimethylpentane (2,3,4-TMP) resulted in a linear dose response, as determined by cellular lactate dehydrogenase leakage. The EC50 for 2,3,4-TMP was 16.3 mM. Metabolite analysis by gas chromatography/mass spectrometry of supernate and cell extracts from cultures exposed to 2,3,4-TMP (12.0 mM) failed to detect the presence of metabolites. Electron-microscopic examination of proximal tubules exposed to 2,3,4-TMP indicated ultrastructural changes that included increased mitochondrial swelling, increased vesiculation, decreased microvilli and pyknotic nuclei. This study indicates that kidney proximal tubules do not appear to metabolize 2,3,4-TMP.

Animals↗

PubMed1990

Lysosomal changes in renal proximal tubular epithelial cells of male Sprague Dawley rats following decalin exposure.

A histochemical stain for acid phosphatase served as a marker for lysosomal alterations in renal tubular cells associated with male rat hyaline droplet nephropathy. Morphometric analysis and quantitative histochemistry were used to compare the size and acid phosphatase stain reaction of lysosomes in tubular epithelial cells of treated and control animals. Decalin exposure increased the size and significantly (p less than 0.01) reduced the acid phosphatase stain intensity of individual lysosomes. However, there was no significant different (p greater than 0.05) between the acid phosphatase stain intensity of treated and control animals when analyzed on a whole cell basis. The increase in size of the lysosomes without a proportional increase in whole cell acid phosphatase stain intensity indicates a dilution or a failure to accommodate in the acid phosphatase concentration (stain intensity/microns 2) per lysosome. All acid phosphatase stain reaction product was contained within intact lysosomes, mitigating against the hypothesis of lysosomal enzyme leakage as the cause of cell death in decalin-induced alpha 2U globulin nephropathy.

Acid Phosphatase↗

PubMed1990

The determination of the repeated oral toxicity of halocarbon oil, series 27-S.

Halocarbon 27-S (HC 27-S), a polymer of chlorotrifluoroethylene (CTFE), is used as a lubricating oil for pumps in hyperbaric chambers. Although monomeric CTFE has been shown to produce renal lesions in rats, the toxicity of CTFE polymers have not been investigated. To assess the toxicity of repeated exposure to HC 27-S, three groups (N = 6/group) of male and female Fischer-344 rats were dosed with 2.5 g HC 27-S/kg for 7 or 21 consecutive days. Groups were sacrificed at 7, 21, and 35 days (14 days after the 21-day dosing). Corresponding control groups (N = 6) were dosed with deionized water. Decreased water consumption and urine output were apparent in all test groups. Statistically significant increases in fluoride excretion were noted in 24-hr urine samples assessed periodically during the study. Neurotoxic signs were observed in female rats but not in male rats. Significant increases in liver and kidney weights were seen in all rats, regardless of number of dosing days. The increased fluoride burden in treated animals appeared sufficient to alter bone calcium/phosphate ratios in male rats but not female rats. Gross liver enlargement and hepatocellular cytomegaly indicated that the liver was probably the primary target organ following repeated administration of HC 27-S.

Animals↗

PubMed1989

In vitro toxicity of solubilized 2,3,4-trimethylpentane. I. Cytotoxicity and metabolism of TMP using primary hepatocytes.

Primary rat hepatocyte suspension cultures (approximately 2 X 10(6) cells) exposed to solubilized 2,3,4-trimethylpentane at concentrations ranging from 7.9 to 31.5 mM under two different culture conditions resulted in a linear dose response, as determined by lactate dehydrogenase leakage and viability data. A significant increase in the 2,3,4-trimethylpentane effective concentration 50 for primary hepatocytes occurred when exposures were implemented in medium containing 0.05% albumin. The effective concentration 50 for hepatocytes exposed to 2,3,4-trimethylpentane in medium lacking and containing albumin were 17.1 and 20.7 mM, respectively. Metabolite analysis by gas chromatography-mass spectrometry of supernatant (lacking or containing albumin) and cell extracts from hepatocyte cultures exposed to 2,3,4-trimethylpentane for 4 h indicated the presence of three metabolites: 2,3,4-trimethyl-1-pentanol, 2,3,4-trimethyl-2-pentanol, 2,3,4-trimethyl-2-pentanol, and 2,3,4-trimethyl-1-pentanoic acid. Electron microscopic examination of 2,3,4-trimethylpentane-exposed primary hepatocytes indicated ultrastructural changes which included abnormal condensed chromatin association with the nuclear membrane, swollen mitochondria, increased amounts of cytoplasmic lipid, significant loss of microvilli from the cell surface, increased vacuolation, and increased numbers of peroxisomes. Although these changes were observed under both culture conditions, they were more severe in cultures lacking albumin. This study indicates that primary hepatocyte suspension cultures provide a useful system for rapidly identifying liver metabolites of selected test compounds of interest.

Animals↗

PubMed1988

Analysis of the biocompatibility of ALCAP ceramics in rat femurs.

Ceramics composed of aluminum, calcium, and phosphorus oxides (ALCAP) were tested for compatibility as bone replacement biomaterials. Implantation of ALCAP ceramics in rat femurs had no deleterious effect on body weights, organ/body weight ratios, muscle, bone, blood, and kidney function. Aluminum resorbed from ALCAP ceramic bone implants was excreted in the urine and was not deposited in adjacent muscle. Plasma levels of aluminum were not elevated in rats implanted with ALCAP ceramics. Alkaline phosphatase activity of excised implant sites indicated greater bone formation in ALCAP ceramic implants than in bone autografts. Radiographs and implant histology demonstrated excellent bone association with implants and ingrowth of new bone into ALCAP ceramic implants. ALCAP ceramics are biocompatible and suitable for reconstruction of bone.

Alkaline Phosphatase↗