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PubMed1993

Application of computerized differentiation technique to remote-sensing Fourier transform infrared spectrometry for analysis of toxic vapors.

A differential method was developed for overcoming the difficulty in collection of background spectra when a remote-sensing FTIR is used during field measurements of air contaminants. A background spectrum was generated by introducing a delta lambda interval for every sampled data point of the spectrum. Temporal variations in spectral intensity caused by instability of the interferometer and changing IR beam configurations were greatly reduced through the use of the differential spectrum. Multicomponent analysis was performed by means of using a least-squares fit program with the differential spectrum. Three sets of spectra were evaluated by use of both the differential technique and the traditional method, which employs a clean background spectrum. There was no significant difference found between these two methods when a clean background spectrum could be used. However, in the case of field air monitoring system evaluations (as opposed to laboratory-based instrument evaluations), clean background spectra are frequently not available. Although the differential technique results in an increase in the limit of detection, results demonstrated that this method has sufficient sensitivity to detect and quantify both individual and mixtures of toxic compounds in the workplace.

Air Pollutants↗
PubMed1999

Site-specific consultation for a chemical mixture.

The Agency for Toxic Substances and Disease Registry (ATSDR) uses the weight of evidence methodology to evaluate interactions of chemical mixtures. In the process, toxicity, toxicokinetics, and toxicodynamics of chemical components of the mixture are carefully examined. Based on the evaluation, predictions are made that can be used in real-life situations at hazardous waste sites. In this paper, health outcomes were evaluated for a mixture of eight compounds that were found at a specific site. These eight chemicals were identified and possibly associated with human exposure. The health assessors could consider similar thought processes when evaluating chemical mixtures at hazardous waste sites.

Aniline Compounds↗
PubMed2003

Determination of polycyclic aromatic hydrocarbons in urine of coke oven workers by headspace solid phase microextraction and gas chromatography-mass spectrometry.

Polycyclic aromatic hydrocarbons (PAHs) represent a complex mixture of toxic compounds that are ubiquitous in the environment. We investigated the utility of head space-solid phase microextraction (HS-SPME) to measure the following surrogate PAHs in urine: naphthalene (NAP), phenanthrene (PHE), pyrene (PYR), and benzo(a)pyrene (BAP), representing classes of 2-, 3-, 4- and 5-ring compounds, respectively. We then applied the method to urine from 28 coke oven workers (median levels (microg/l) were: NAP=3.65, PHE=1.51, PYR=0.003, BAP not detected) and 22 controls (median (microg/l) NAP=0.859, PHE=0.062, PYR=0.001, BAP not detected). Urinary levels of NAP, PHE, and PYR were all associated with exposure category (controls, side- and bottom-workers, and top-workers) but not with smoking status. Strong correlations were observed between urinary levels of NAP, PHE, and PYR in coke-oven workers. Our results indicate that unmetabolized 2-, 3- and 4-ring PAHs can be measured in urine by HS-SPME. Such measurements can be used to investigate the uptake and metabolism of complex PAH mixtures in humans.

Adolescent↗
PubMed2002

An analysis of the combined effects of organic toxicants.

This paper presents a basic database for the joint actions of 44 binary mixtures of various organic toxicants on Escherichia coli. The multiple toxicity behaviors observed from the E. coli organisms were analyzed and compared with previous works based on the Microtox tests. The two kinds of tests produced quite different responses, in terms of the joint action mode and the sum of toxic units, to various organic mixtures. However, detailed analyses with the considerations of the chemical's mechanisms of toxicity and the slope of toxicant's dose-response curve have revealed several general criteria for the prediction of combined effects of organic toxicants. First, for both reactive and non-reactive toxicants, either additive or less than additive (antagonistic) joint actions will be observed for chemicals of the same mechanism of toxicity. Second, the mixture of reactive toxicants with different mechanisms is the only category of organic mixtures associated with frequent observations of synergism. Third, greater-than-additive (synergistic) effects are inherently associated with toxicants having flat dose-response curves. Less than additive effects are, however, mainly related to a chemical's display steep dose-response curves. Model analyses indicate that the observed synergistic effects are due to response addition or response multiplication joint actions. Hence, most of the synergistic joint actions are non-interactive in nature and are governed by the dose-response relationships of individual toxicants.

Databases, Factual↗
PubMed1999

Toxicity study of a rubber antioxidant, mixture of 2-mercaptomethylbenzimidazoles, by repeated oral administration to rats.

2-Mercaptobenzimidazole (2-MBI), a rubber antioxidant, is known to exhibit potent antithyroid toxicity in rats and is a candidate as an environmental endocrine disrupter. 2-Mercaptomethylbenzimidazoles (a 1:1 mixture of 4-methyl and 5-methyl isomers, MMBIs), are also employed industrially as rubber antioxidants and are suspected to exert antithyroid toxicity such as 2-MBI. In this investigation, acute and subacute oral toxicity studies of MMBIs in Wistar rats were conducted. The clinical signs of acute oral toxicity were observed including decreased spontaneous movement, a paralytic gait, salivation and lacrimation, and adoption of prone and lateral positions. The LD50 was estimated to be 330 mg/kg. In the subacute oral toxicity study, male and female rats were treated with MMBIs by gavage at doses of 0 (corn oil), 4, 20 and 100 mg/kg for 28 consecutive days followed by a 2-week recovery period for the control and highest dose groups. Body weight and food consumption, clinical signs, organ weights, clinical biochemistry and haematological parameters including clotting times and micronuclei induction in bone marrow erythropoeitic cells, and histopathology were examined. Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg. Male rats administered 100 mg/kg MMBIs exhibited a 1.8-fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MMBIs/kg exhibited significant increases of liver and kidney but not thyroid weights, and serum cholesterol level. The antithyroid toxicity of MMBIs in rats was estimated to be one-tenth that of 2-MBI. No-observed-effect levels for male and female rats were found to be 4 and 20 mg/kg, respectively, in this subacute oral toxicity study.

Animals↗
PubMed1995

Interactive cytotoxicities of selected organic and inorganic substances to brown cells of Mercenaria mercenaria.

Toxicities of binary mixtures of Cu2+, Cd2+, benzo(a)pyrene [B(a)P] and N-ethylmaleimide (NEM) were screened using the in vitro neutral red (NR) assay to test the hypothesis that combined toxicity is more than or less than additive relative to the influence of each mixture constituent on toxicant uptake and brown cell lysosomal membrane stability. Significant cytotoxicity was observed at 25 mumol/L Cu2+, 500 mumol/L Cd2+ and 25 mumol/L NEM. B(a)P at 12 mumol/L exerted no toxicity under the conditions of the assay. Interactions between Cu2+ and NEM, between Cd2+ and NEM, and between Cd2+ and B(a)P significantly influenced brown cell survival. Comparison of observed joint toxicity with estimates made using a model of independent joint action indicates that interactive effects are less than additive in character. The 3-way interaction involving Cu2+, B(a)P, and NEM also affected brown cell survival to a statistically significant degree. However, the interactive cytotoxicity of this mixture is attributable mainly to the combined effect of Cu2+ and NEM. Results also indicate that new hypothesis and additional experimentation are needed to understand the interactive toxicity of mixture constituents.

Analysis of Variance↗
PubMedDate not supplied

Inhalation toxicity study of methanol, toluene, and methanol/toluene mixtures in rats: effects of 28-day exposure.

The inhalation toxicity of methanol and toluene was investigated in rats. Young Sprague Dawley rats of both sexes were exposed to vapors of methanol (300 ppm, 3000 ppm), toluene (30 ppm, 300 ppm) or methanol/toluene (300/30 ppm, 300/300 ppm, 3000/30 ppm, and 3000/300 ppm) six hrs per day, five days/week for four weeks. Control animals inhaled air only. Increased serum alkaline phosphatase activity was observed in males exposed to high-dose toluene, and decreased creatinine was noted in the group exposed to high-dose methanol/toluene. The thyroid gland in females appeared to be a target organ for inhaled methanol, toluene, and methanol/toluene, although the changes were confined to a mild, and occasionally moderate, reduction in follicle size. Histopathological changes of the nasal passages, consisting of subepithelial nonsuppurative inflammation, occurred in higher incidences in rats exposed to methanol/toluene than in those exposed to the individual vapors. Inhalation of methanol, toluene, or methanol/toluene produced no changes in liver weights, hepatic mixed-function oxidases, or serum aspartate transaminase activities, and onlly minimal changes in liver histopathology. The only liver changes were decreased liver weight and increased cytoplasmic density of the periportal areas in females exposed to high-dose methanol/toluene. These data indicated that exposure to methanol, toluene, or a mixture of both produced mild biochemical effects and histological changes in the thyroid and nasal passage. No apparent interactive effects were observed.

Administration, Inhalation↗
PubMed2000

Developmental toxicity of carbon black oil in mice.

BACKGROUND: Carbon black oil (CBO) is a refinery side-stream product used to produce asphalt and other commercial products. CBO contains several classes of hydrocarbons, several of which are known to exhibit systemic and gestational toxicities, making this mixture a candidate for causing reproductive toxicity. METHODS: Swiss-Webster mice were administered CBO (300, 350, 400 mg/kg/day) via oral gavage in a dosage volume of 10 microl/g body weight on gestation days (GD) 6-15. Uterine contents were evaluated on GD 18. RESULTS: Treatment with CBO at all dosage levels resulted in a high frequency of maternal clinical symptoms and a decrease in maternal weight gain. Decreased fetal viability was observed, manifested as a decrease in viable implants and, in a high percentage of treated dams, as early resorption of the entire litter. A significant reduction in fetal weight was also observed. However, neither structural malformations nor developmental delays in ossification were observed in any of the living offspring. To minimize maternal toxicity, the dosage range was lowered (100, 200, 300 mg/kg/day), and the concentration was adjusted such that the volume administered to each dam was decreased by 20%. In this trial, the only maternal effect observed was an increase in maternal liver weight at 200 and 300 mg/kg. The fetal lethality effects observed previously were reduced substantially. Nevertheless, the frequency of resorption among all treatment groups was higher statistically than in controls. CONCLUSIONS: These data support the hypothesis that CBO is reproductively toxic in Swiss-Webster mice at oral doses of >/=100 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Cytogenetic studies on commercial hexane solvent.

Commercial hexane is a solvent mixture of six-carbon isomers, consisting principally of n-hexane, 3-methylpentane, methylcyclopentane and 2-methylpentane. The potential of commercial hexane to produce chromosome aberrations was evaluated in both an in vitro assay using Chinese hamster ovary (CHO) cells and an in vivo cytogenetics assay using Sprague-Dawley rats. The CHO cells were exposed to media containing commercial hexane at concentrations of 0.014-0.42 microliters ml-1 in the presence and absence of an S-9 activation mixture. Cellular toxicity was observed at the higher dose levels, but no increase in chromosome aberrations was observed in either the non-activated or S-9-activated systems. For the in vivo cytogenetics assay, rats were exposed nose-only for 6 h per day for 5 consecutive days to commercial hexane vapor at target concentrations of 900, 3000 and 9000 ppm. Bone marrow cells were collected at 6 and 24 h after the midpoint of the last exposure. Metaphase cells were examined microscopically for chromosome aberrations. No statistically significant increases in aberrant cells were observed in the commercial hexane-exposed animals of any dose group at either of the bone marrow harvest times. In conclusion, commercial hexane did not produce chromosomal mutations under the conditions of these studies.

Animals↗
PubMed2005

Prostaglandin-induced neurodegeneration is associated with increased levels of oxidative markers and reduced by a mixture of antioxidants.

Prostaglandin E2 (PGE2), one product of inflammatory reactions, and PGA1, which is formed during PGE2 extraction, induce degeneration in adenosine 3',5'-cyclic monophosphate (cAMP)-induced differentiated neuroblastoma (NB) cells in culture. The mechanisms of action of PGE2 on neurodegeneration are not well understood. To investigate this, we have utilized PGA(1), which mimics the effect of PGE2 and is very stable in solution. We have assayed selected markers of oxidative stress such as heme oxygenase-1 (HO-1), catalase, glutathione peroxidase (GPx1), mitochondrial superoxide dismutase (Mn-SOD-2) and cytosolic superoxide dismutase (Cu/Zn-SOD-1). The results showed that the treatment of differentiated NB cells with PGA1 for a period of 48 hr increased the expression of HO-1 and catalase, decreased the expression of GPx1 and Mn-SOD-2, and did not change the expression of Cu/Zn-SOD-1 as measured by gene array and confirmed by real-time PCR. The protein levels of HO-1 and GPx1 increased; however, the protein level of Mn-SOD-2 decreased and the levels of catalase and Cu/Zn-SOD-1 did not change as determined by Western blot. The increases in the levels of HO-1 and GPx1 reflected an adaptive response to increased oxidative stress, whereas decrease in the level of Mn-SOD-2 may make cells more sensitive to oxidative damage. These data suggest that one of the mechanisms of action of PGA1 on neurodegeneration may involve increased oxidative stress. This was supported further by the fact that a mixture of antioxidants (alpha-tocopherol, vitamin C, selenomethionine, and reduced glutathione), but not the individual antioxidants, reduced the level of PGA1-induced degeneration in differentiated NB cells. The addition of a single antioxidant at two or four times the concentration used in the mixture was toxic.

Adaptation, Physiological↗
PubMed2004

Cytogenetic effects of leachates from tannery solid waste on the somatic cells of Vicia faba.

The contamination of surface- and groundwater by the leaching of solid wastes generated by industrial activities as a result of water runoff and rainfall is a matter of great concern. The leachates from tannery solid waste (TSW), a major environmental pollutant, were examined for their possible genotoxic effects on the somatic cells of Vicia faba. Leachates were prepared from solid wastes procured from leather-tanning industrial sites, and V. faba seedlings were exposed to three test concentrations, 2.5%, 5%, and 10%, through soil and aqueous media for 5 days. The root tips examined for cytogenetic damage revealed that leachate of TSW significantly inhibited the mitotic index and induced significantly frequent chromosomal and mitotic aberrations (CA/MA) in a dose-dependent manner. The chemical analysis of TSW samples revealed that the chief constituents were chromium and nickel, which may cause genetic abnormalities. The frequency of aberrations was found to be higher in the root meristematic cells of Vicia faba exposed through the aqueous medium than those exposed through the soil medium. The results of the present study indicated that contamination of potable water bodies by leachates of TSW may cause genotoxicity. For the biomonitoring of complex mixtures of toxicants with the V. faba bioassay, the use of the aqueous medium seems to be a more promising method than the use of the soil medium.

Chromosome Aberrations↗
PubMed2002

Proposal for single and mixture biological exposure limits for sevoflurane and nitrous oxide at low occupational exposure levels.

OBJECTIVES: Assessment of individual exposures to sevoflurane plus nitrous oxide (N(2)O) by biological monitoring of unmodified analytes in post-shift urine of exposed personnel. METHODS: Anaesthetics in urine and breathing area were monitored in 124 subjects in 11 operating theatres. Passive samplers were collected after 2.5-7 h of exposure, at the same time as post-shift urinary samples, to evaluate the individual time-weighted average (TWA) exposures to sevoflurane and N(2)O. A static headspace sampler coupled with a gas chromatograph mass spectrometer was used for analytical determinations (sensitivity sufficient to reveal biological/environmental exposures of 0.1 microg/l(urine) and 50 ppb for sevoflurane, and 1 microg/l(urine) and 80 ppb for N(2)O). RESULTS: Median (range) post-shift urinary and environmental values were 1.2 microg/l(urine) (0.1-5.0) and 0.4 ppm (0.05-3.0) for sevoflurane ( n=107) and 10.9 microg/l(urine) (0.5-74.9) and 8.6 ppm (0.2-123.4) for N(2)O ( n=121) (all low-exposure range). At log-log regression, urinary levels closely correlated with environmental data (sevoflurane, r(2)=0.7538; N(2)O, r(2)=0.8749). Biological equivalent limits (BELs) based on National Institute for Occupational Safety and Health (NIOSH) TWA exposure limits, calculated as means of regression slope and y-intercept, were 3.6 microg/l(urine) for sevoflurane (corresponding to 2 ppm) and 22.3 microg/l(urine) for N(2)O (corresponding to 25 ppm). Individual "mixture BELs", which we calculated by applying the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) mix formula to biomarker values and using the obtained NIOSH-based BELs as a reference, closely correlated with mixture TLVs (rho=0.816, Lin's concordance test). CONCLUSIONS. We propose urinary sevoflurane as a new, specific, internal dose biomarker for routine biological monitoring of personal exposures among operating-theatre personnel, and use of reliable "mixture BELs" to provide safer levels of internal exposure for workers exposed to mixtures of sevoflurane and N(2)O, and conceivably also to other mixtures of toxicants with possible additive effects.

Environmental Monitoring↗
PubMed1994

Gangliosides--a new therapeutic agent against stroke and Alzheimer's disease.

Gangliosides are glycosphingolipids localized to the outer leaflet of the plasma membrane of vertebrate cells. The highest ganglioside concentration of any organ is found in the mammalian brain, where the gangliosides are enriched in the neuronal membrane, particularly in the synapses. There are four major brain gangliosides with the same neutral tetrasaccharide core to which one to three sialic acids are linked--the simplest being the GM1-ganglioside. These gangliosides have been shown to have neuritogenic and neuronotrophic activity and to facilitate repair of neuronal tissue after mechanical, biochemical or toxic injuries. Mixtures of native bovine brain gangliosides were adopted for pharmacological use in the treatment of peripheral nerve damage, and GM1-ganglioside has been applied for the treatment of CNS injuries and diseases. Beneficial effects of GM1 have been documented in the treatment of stroke and spinal cord injuries, particularly when the treatment has been initiated within a few hours of the acute event. Continuous intraventricular infusion of GM1 has recently been shown to have a significant beneficial effect in Alzheimer disease of early onset (AD Type I).

Alzheimer Disease↗
PubMed1994

Toxic responses to defined chemical mixtures: mathematical models and experimental designs.

The problem and relevance of assessing biological responses to chemical mixtures is presented with reference to the literature on this problem and its possible solutions. This review is intended for a general audience as an introduction to, and comment on, assessing the interactions of defined mixtures of xenobiotics. The focus is on experimental toxicology, however, the methods are also applicable to pharmacology. Much of the literature on this topic is quite specialized in statistics, theory, or specific applications. This may deter a significant portion of the growing number of investigators in this field from using this literature, and may partially account for the persistent use of methods which have been shown to permit precarious conclusions. References are given for some of the most comprehensive and recent work and reviews on the subject. The reader is given some familiarity with this topic's basic problems and ideas, and the controversy on terminology. One example is presented of a popular experimental design and data analysis method which while applicable in some situations, has been shown to lead to precarious and even erroneous conclusions. Eight other methods of data analysis are briefly presented and some of their advantages, disadvantages, assumptions, and limitations are discussed. These methods were selected to illustrate similarities and differences in the various approaches taken in addressing this problem. Three basic types of experimental design appropriate to these kinds of studies are outlined. General considerations, suggested guidelines, and possible pitfalls in experimental design, and data analysis of biological responses to chemical mixtures are discussed.

Chemical Phenomena↗