Showing papers in "Environmental Health Perspectives in 1984"

Paraquat: model for oxidant-initiated toxicity.

Abstract: Paraquat, a quaternary ammonium bipyridyl herbicide, produces degenerative lesions in the lung after systemic administration to man and animals. The pulmonary toxicity of paraquat resembles in seve...

A carcinogenic potency database of the standardized results of animal bioassays

Abstract: The preceding paper described our numerical index of carcinogenic potency, the TD50 and the statistical procedures adopted for estimating it from experimental data. This paper presents the Carcinogenic Potency Database, which includes results of about 3000 long-term, chronic experiments of 770 test compounds. Part II is a discussion of the sources of our data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Part III is a guide to the plot of results presented in Part IV. A number of appendices are provided to facilitate use of the database. The plot includes information about chronic cancer tests in mammals, such as dose and other aspects of experimental protocol, histopathology and tumor incidence, TD50 and its statistical significance, dose response, author's opinion and literature reference. The plot readily permits comparisons of carcinogenic potency and many other aspects of cancer tests; it also provides quantitative information about negative tests. The range of carcinogenic potency is over 10 million-fold.

The TD50: a proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments.

Abstract: A generally accepted format for the numerical description of the carcinogenic potency of a particular chemical in a particular strain of animals is desirable so that statements from different sources about potency and attempts by different authors to correlate potency with particular laboratory measurements will be comparable. The choice of an appropriate standard format is to a certain extent arbitrary. In this paper we recommend that the TD50 (tumorigenic dose rate 50) be used. TD50 can be calculated for a single target site or combination of sites. The TD50, in analogy with the LD50, is defined as that chronic dose rate (in mg/kg body weight/day) which would halve the actuarially adjusted percentage of tumor-free animals at the end of a standard experiment time--the "standard lifespan" for the species. This paper consists of a brief discussion of the TD50, sufficient to make the general reader familiar with the properties of such an index, an appendix discussing methods for its estimation and certain conventions we have adopted for use in analyzing "nonstandard" experiments. A major problem in calculating any index of carcinogenic potency is that much published material gives only the final crude percentage of tumor-bearing animals at each dose, instead of percentages adjusted for the effects of intercurrent mortality or data from which these adjusted percentages can be derived. If the dose level administered to the animals is toxic, then premature death from nonneoplastic causes may prevent some dosed animals that would have developed tumors from actually doing so. This will particularly affect the high-dose group.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of bronchoalveolar lavage to detect lung damage

Abstract: The assay of bronchoalveolar washings from acutely exposed animals has proven useful as a rapid screen for lung injury from inhaled airborne toxins. The screen is useful for choosing appropriate compounds and exposure levels for subsequent in-depth studies in which complete histopathologic evaluations will be made. An inflammatory response can be detected by the appearance of polymorphonuclear leukocytes and an increase in protein content of lung washings. The release of the cytoplasmic enzyme, lactate dehydrogenase, into the acellular portion of the lavage fluid serves as an indication of cell death or membrane damage. A large increase in some lysosomal enzymes has been found in the bronchoalveolar lavage fluids from animals chronically exposed to insoluble particles. Angiotensin-converting enzyme has been found to be elevated in bronchoalveolar washings from animals with endothelial cell damage in the pulmonary capillaries. The correlation of these cellular and biochemical alterations in the bronchoalveolar lavage fluid with morphological indications of damage has served to validate this method of detecting acute lung injury. Further study is needed to validate indicators of developing chronic disease.

Absorption of some glycol ethers through human skin in vitro

Abstract: To assist evaluation of the hazards of skin contact with selected undiluted glycol ethers, their absorption across isolated human abdominal epidermis was measured in vitro. Epidermal membranes were set up in glass diffusion cells and, following an initial determination of permeability to tritiated water, excess undiluted glycol ether was applied to the outer surface for 8 hr. The appearance of glycol ether in an aqueous "receptor" phase bathing the underside of the epidermis was quantified by a gas chromatographic technique. A final determination of tritiated water permeability was compared with initial values to establish any irreversible alterations in epidermal barrier function induced by contact with the glycol ethers. 2-methoxyethanol (EM) was most readily absorbed (mean steady rate 2.82 mg/cm2/hr), and a relatively high absorption rate (1.17 mg/cm2/hr) was also apparent for 1-methoxypropan-2-ol (PM). There was a trend of reducing absorption rate with increasing molecular weight or reducing volatility for monoethylene glycol ethers (EM, 2.82 mg/cm2/hr; 2-ethoxyethanol, EE, 0.796 mg/cm2/hr; 2-butoxyethanol, EB, 0.198 mg/cm2/hr) and also within the diethylene glycol series: 2-(2-methoxyethoxy) ethanol (DM, 0.206 mg/cm2/hr); 2-(2-ethoxyethoxy) ethanol (DE, 0.125 mg/cm2/hr) and 2-(2-butoxyethoxy) ethanol (DB, 0.035 mg/cm2/hr). The rate of absorption of 2-ethoxyethyl acetate (EEAc) was similar to that of the parent alcohol, EE. Absorption rates of diethylene glycol ethers were slower than their corresponding monoethylene glycol equivalents. Combination of intrinsic toxicity and ability to pass across skin contribute to assessment of hazards of contact with undiluted glycol ethers.

Cadmium and the kidney.

Abstract: The paper reviews certain aspects of importance of cadmium and the kidney regarding the assessment of risks and understanding of mechanisms of action. The review discusses the following topics: history and etiology of cadmium-induced kidney dysfunction and related disorders; cadmium metabolism, metallothionein and kidney dysfunction; cadmium in urine as indicator of body burden, exposure and kidney dysfunction; cadmium levels in kidney and liver as indicators of kidney dysfunction; characteristics of early kidney dysfunction; the critical concentration concept; critical concentrations of cadmium in kidney cortex; and prognosis. 99 references, 7 figures.

Statistical Issues in the Design, Analysis and Interpretation of Animal Carcinogenicity Studies

Abstract: Statistical issues in the design, analysis and interpretation of animal carcinogenicity studies are discussed. In the area of experimental design, issues that must be considered include randomization of animals, sample size considerations, dose selection and allocation of animals to experimental groups, and control of potentially confounding factors. In the analysis of tumor incidence data, survival differences among groups should be taken into account. It is important to try to distinguish between tumors that contribute to the death of the animal and "incidental" tumors discovered at autopsy in an animal dying of an unrelated cause. Life table analyses (appropriate for lethal tumors) and incidental tumor tests (appropriate for nonfatal tumors) are described, and the utilization of these procedures by the National Toxicology Program is discussed. Despite the fact that past interpretations of carcinogenicity data have tended to focus on pairwise comparisons in general and high-dose effects in particular, the importance of trend tests should not be overlooked, since these procedures are more sensitive than pairwise comparisons to the detection of carcinogenic effects. No rigid statistical "decision rule" should be employed in the interpretation of carcinogenicity data. Although the statistical significance of an observed tumor increase is perhaps the single most important piece of evidence used in the evaluation process, a number of biological factors must also be taken into account. The use of historical control data, the false-positive issue and the interpretation of negative trends are also discussed.

Structure of mammalian metallothionein.

Abstract: All mammalian metallothioneins characterized contain a single polypeptide chain of 61 amino acid residues, among them 20 cysteines providing the ligands for seven metal-binding sites. Native metallothioneins are usually heterogeneous in metal composition, with Zn, Cd, and Cu occurring in varying proportions. However, forms containing only a single metal species, i.e., Zn, Cd, Ni, Co, Hg, Pb, Bi, have now been prepared by in vitro reconstitution from the metal-free apoprotein. By spectroscopic analysis of such derivatives it was established that all cysteine residues participate in metal binding, that each metal ion is bound to four thiolate ligands, and that the symmetry of each complex is close to that of a tetrahedron. To satisfy the requirements of the overall Me7(Cys-)20 stoichiometry, the complexes must be combined to form metal-thiolate cluster structures. Experimental proof for the occurrence of such clusters comes from the demonstration of metal-metal interactions by spectroscopic and magnetic means. Thus, in Co(II)7-metallothionein, the Co(II)-specific ESR signals are effectively suppressed by antiferromagnetic coupling of juxtaposed paramagnetic metal ions. By monitoring changes in ESR signal size occurring on stepwise incorporation of Co(II) into the protein, it is possible to follow the building up of the clusters. This process is biphasic. Up to binding of four equivalents of Co(II), the ESR amplitude increases in proportion to the metal content, indicating generation of magnetically noninteracting high-spin complexes. However, upon addition of the remaining three equivalents of Co(II), these features are progressively suppressed, signaling the formation of clusters. The same mode of cluster formation has also been documented for Cd and Hg. The actual spatial organization of the clusters and the polypeptide chain remains to be established. An attractive possibility is the arrangement of the tetrahedral metal-thiolates in adamantane-like structures surrounded by properly folded segments of the chain providing the ligands. 1H-NMR data and infrared absorption measurements are consistent with a tightly folded structure rich in beta-type conformation.

Testicular toxicity produced by ethylene glycol monomethyl and monoethyl ethers in the rat.

Abstract: Ethylene glycol monomethyl ether (EGME) and ethylene glycol monoethyl ether (EGEE) were administered orally to young male rats at doses varying from 50 to 500 mg/kg/day and 250 to 1000 mg/kg/day for EGME and EGEE, respectively, for 11 days. At sequential times animals were killed and testicular histology examined. The initial and major site of damage following EGME treatment was restricted to the primary spermatocytes undergoing postzygotene meiotic maturation and division. EGEE produced damage of an identical nature, but a larger dose was required to elicit equivalent severity (500 mg EGEE/kg being approximately equivalent to 100 mg EGME/kg). Additionally, within the spermatocyte population, differential sensitivity was observed depending on the precise stage of meiotic maturation: dividing (stage XIV) and early pachytene (stages I-II) greater than late pachytene (stages VIII-XIII) greater than mid-pachytene (stages III-VII). Equivalent doses of methoxyacetic acid (MAA) and ethoxyacetic acid (EAA) gave injury similar to the corresponding glycol ether. When animals were pretreated with inhibitors of alcohol metabolism followed by a testicular toxic dose of EGME (500 mg/kg), an inhibitor of alcohol dehydrogenase (pyrazole) offered complete protection. Pretreatment with the aldehyde dehydrogenase inhibitors disulfiram or pargyline did not ameliorate the testicular toxicity of EGME. In mixed cultures of Sertoli-germ cells, MAA and not EGME produced effects on spermatocytes analogous to that seen in vivo, at concentrations approximately equivalent to steady-state plasma levels after a single oral dose of EGME (500 mg/kg). It would seem likely that a metabolite (MAA or possibly methoxyacetaldehyde) and not EGME is responsible for the production of testicular damage.

Cell Calcium, Cell Injury and Cell Death

Abstract: The role of calcium in cell injury has been the subject of much recent investigation. The movement and redistribution of this cation from extra to intracellular compartments and the calcium shifts between intracellular compartments may well play a determinate role in the cell's reaction to injury. Therefore, data of such shifts and their correlation with morphological, biochemical and cytoskeletal studies will provide a better understanding of these processes. To study the effects of calcium regulation on acute lethal anoxic injury and the effects of inhibition of respiration with cyanide, three experimental systems were utilized: Ehrlich ascites tumor cells, isolated rabbit proximal tubule segments and suspended or cultured rat proximal tubule cells. Although our data showed no correlation between total cell calcium and cell death except in highly selected cell systems, they did indicate that calcium can be an important control variable. Therefore, massive increases in total cell calcium, as seen in Ca3(PO4)2 precipitation in mitochondria, must be a secondary event and represent the modern day equivalent of the classical dystrophic calcification seen by pathologists in the past. Although the involvement of extracellular calcium in cell death may well be significant in some cell types, redistribution of calcium within the intracellular compartments may play an even more important role.

Comparative inhalation teratogenicity of four glycol ether solvents and an amino derivative in rats.

Abstract: Previous research demonstrated the inhalation teratogenicity of the solvent 2-ethoxyethanol in rats and rabbits. As this is one of a class of widely used industrial solvents, we investigated the teratogenicity of five structurally related compounds. Each chemical was vaporized and administered to approximately 15 pregnant rats in one to three concentrations for 7 hr/day on gestation days 7 to 15, and dams were sacrificed on day 20. Fetuses were individually weighed, and two-thirds of them were fixed in Bouin's solution and examined for soft-tissue anomalies. The other one-third were fixed in alcohol, stained with Alizarin Red and examined for skeletal defects. Data were analyzed on a litter basis; three solvents were compared with a pooled group (N = 34) of sham-exposed controls, and the remaining two were compared with a group of 15 controls. At concentrations which were apparently not maternally toxic, 2-methoxyethanol was highly embryotoxic, producing complete resorptions at 200 ppm; increased resorptions, reduced fetal weights and skeletal and cardiovascular defects occurred at both 100 and 50 ppm. 2-ethoxyethyl acetate at 600 ppm induced complete resorption of litters; 390 ppm reduced fetal weights and induced skeletal and cardiovascular defects, but only a single defect was observed at 130 ppm. 2-Butoxyethanol evidenced slight maternal toxicity at 200 ppm but produced no increase in congenital defects at that concentration. Neither 2-(2-ethoxyethoxy)ethanol (100 ppm) nor 2-methylaminoethanol (150 ppm) was maternally toxic or embryotoxic. In summary, shorter alkyl chained glycol ethers produced greater embryotoxicity than those having longer chains, and the ester produced effects equivalent to the ether, both patterns predictable from the biochemical literature.

General aspects of cadmium: transport, uptake and metabolism by the kidney

Abstract: Cadmium taken up from lung and gastrointestinal tract is transported via blood to liver and kidney On long-term exposure to cadmium, renal tubular dysfunction develops in humans and experimental animals Data from animal experiments demonstrate that initially after exposure cadmium in blood is bound to albumin and proteins with higher molecular weight Such cadmium is mainly taken up in liver For a few days after exposure cadmium exists as metallothionein in plasma and blood cells After both single and long-term administration of cadmium bound to metallothionein, cadmium is taken up by the kidney The concentration of metallothionein-bound cadmium in plasma is quite low due to continuous renal clearance Cadmium from metallothionein is taken up in renal tubules by pinocytosis and subsequently degraded in lysosomes, thereby releasing cadmium which stimulates de novo synthesis of metallothionein but also binds to reabsorbed metallothionein Catabolizing and rebinding are continuous and prevent excretion of cadmium Because of differences in transport, renal metabolic handling forms of cadmium are also different for different forms of cadmium administered and rate of administration A single dose of metallothionein-bound cadmium given intravenously is almost immediately and completely taken up in the renal tubule Under such conditions, resynthesis and rebinding processes are insufficient to sequester cadmium from sensitive tissue receptors, and renal damage occurs at total tissue concentrations much lower than when renal cadmium concentrations rise slowly This explains the wide range (10-200 micrograms Cd/g wet weight) of cadmium in the renal cortex that associated with renal tubular dysfunction in experimental animals

Pulmonary and generalized lysosomal storage induced by amphiphilic drugs.

Abstract: Administration of amphiphilic drugs to experimental animals causes formation of myelinoid bodies in many cell types, accumulation of foamy macrophages in pulmonary alveoli and pulmonary alveolar proteinosis. These changes are the result of an interaction between the drugs and phospholipids which leads to an alteration in physicochemical properties of the phospholipids. Impairment of the digestion of altered pulmonary secretions in phagosomes of macrophages results in accumulation of foam cells in pulmonary alveoli. Impairment of the metabolism of altered phospholipids removed by autophagy induces an accumulation of myelinoid bodies. The administration of amphiphilic compounds thus causes pulmonary intra-alveolar histiocytosis which is a part of a drug-induced lysosomal storage or generalized lipidosis. The accumulation of drug-lipid complexes in myelinoid bodies and in pulmonary foam cells may lead to alteration of cellular functioning and to clinical disease. Currently over 50 amphiphilic drugs are known. Unique pharmacological properties necessitate clinical use of some of these drugs. The occurrence and severity of potential clinical side effects depend on the nature of each drug, dosage and duration of treatment, simultaneous administration of other drugs and foods, individual metabolic pattern of the patient and other factors. Further studies on factors preventing and potentiating adverse effects of amphiphilic drugs are indicated.

The alveolar macrophage.

Abstract: The pulmonary macrophagic system is critical to the defense of the lung, keeping the alveoli clean and sterile and responding on demand with an adaptive outpouring of new cells into the air sacs. Under basal conditions alveolar macrophages, in common with other mononuclear phagocytes, are derived from the bone marrow. A population of macrophage precursors within the pulmonary interstitium provides a reserve pool capable of proliferation and delivery of phagocytes in response to unusually heavy loads of inhaled particles. This reserve system also produces macrophages when monocytic precursors in the bone marrow are depleted by diseases such as leukemia. The alveolar macrophage is destined to ingest particulate matter and to be eliminated along the mucociliary pathway; clearance by lymphatics is of minor importance and macrophages probably do not recross the alveolar epithelium to reach the pulmonary interstitial compartment. Although the protective role of the macrophage is dominant, this cell may participate, directly or indirectly, in the genesis of two major groups of chronic pulmonary disease, interstitial fibrosis and emphysema. Such inappropriate responses involve interactions with fibroblastic cells and tissue injury initiated by proteases secreted by the macrophage.

Drug-induced pulmonary fibrosis.

Abstract: The lung is a primary target of cell injury in patients receiving cytotoxic drugs, and in many cases the reaction is severe enough to produce diffuse pulmonary fibrosis. Although many different agents may damage the lung, the patterns of cellular injury and repair are relatively constant. Using bleomycin toxicity as an example, it has been shown that, after IV injection, the selective site of lung injury is the vascular endothelium; this is followed by the accumulation of interstitial edema and later by necrosis of Type I epithelial cells. In normal repair, rapid proliferation of Type II cells, followed by differentiation to Type I, restores the epithelial surface without fibrosis. However, after bleomycin, Type II cell proliferation is frequently followed by abnormal differentiation to a metaplastic form of epithelium. Fibroblast proliferation accompanies this abnormal epithelial response which is related either to selective retention of bleomycin by epithelial cells or to the toxic effects of administering more drug at the time of Type II cell division. It is concluded that diffuse interstitial fibrosis results from prolonged disturbance of the normal epithelial-mesenchymal interrelationships at the alveolar wall. Disruption of the fibroblastic control system by extensive epithelial necrosis or by delayed or inappropriate repair may be the key factor in instigating fibroblast proliferation and subsequent deposition of collagen. This mechanism may account for the development of diffuse fibrosis or fibrosing alveolitis in response to a variety of pulmonary toxins.

Experimental studies on toxicity of ethylene glycol alkyl ethers in Japan.

Abstract: Past studies on the toxicological effects of ethylene glycol alkyl ethers as well as the recent data on these chemicals in Japan are reviewed. Only a few researchers have participated in the study of ethylene glycol alkyl ethers in Japan. The effects of ethylene glycol alkyl ethers on testis and embryotoxic effects of ethylene glycol monomethyl ether (EGM) have been studied, as has the teratogenicity of ethylene glycol dimethyl ether (EGdM). Studies on ethylene glycol alkyl ethers and related compounds administered to mice by oral gavage revealed the occurrence of testicular atrophy and decreased white blood cell count by EGM, EGdM, ethylene glycol monomethyl ether acetate, ethylene glycol monoethyl ether and ethylene glycol monoethyl ether acetate, and the toxicity was related to their chemical structure. On the other hand, ethylene glycol, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monoacetate or ethylene glycol diacetate showed no such an effect. Studies on EGM using hamsters or guinea pigs revealed the occurrence of testicular atrophy similar to that observed in mice. In regard to the methyl ethers of other glycols, there is no convincing evidence that propylene glycol monomethyl ether, diethylene glycol monomethyl ether or diethylene glycol dimethyl ether causes testicular atrophy in mice. Teratological studies of EGM and EGdM revealed embryotoxic effects in mice.

Histopathology of early effects of oral cadmium in the rat kidney.

Abstract: Adult male Wistar rats were given 50 ppm Cd in drinking water over a period of 1-24 weeks. The rats were killed and the cadmium concentration of whole blood, blood plasma red cells, liver and kidneys estimated. The plasma metallothionein concentration was measured by radioimmunoassay. Kidney samples were taken for light, transmission and scanning electron microscopic examination. The accumulation of cadmium in the tissues was shown by a linear increase with time, after exposure for 12 weeks. Plasma Cd concentrations showed a clear increase after 3 weeks and preliminary investigation suggests that most is present as Cd-thionein. Early pathological changes in the rat kidney were seen around the 4-6 week period which coincided with the distinct rise in plasma Cd. At 12 weeks, signs of tubular necrosis, interstitial fibrosis and glomerular epithelial cell hypertrophy were present in small areas of the cortex. By 24 weeks, the renal cortex showed clear evidence of tubulo-interstitial nephritis at a Cd concentration of 60 micrograms Cd/g wet weight.

A search for a threshold in the relationship of air pollution to mortality: a reanalysis of data on London winters.

Abstract: The relationship between air pollution and increased risk of mortality has been explored previously using data on 14 winters in London. The results of these analyses have been used to determine a no-observable-effects level. This reanalysis of the data finds no evidence to support the existence of a no-effects level. Further, the reanalysis suggests that the estimated pollution-mortality relationship exists even in nonepisodic winters, when British Smoke readings were less than 500 micrograms/m3.

Isolation and culture of pulmonary endothelial cells.

Abstract: Methods for isolation, identification and culture of pulmonary endothelial cells are now routine. In the past, methods of isolation have used proteolytic enzymes to detach cells; thereafter, traditional methods for cell passaging have used trypsin/EDTA mixtures. Cells isolated and passaged using proteolytic enzymes have been useful in establishing the field and in verifying certain endothelial properties. However, there is a growing awareness of the role of endothelial cells in processing vasoactive substances, in responding to hormones and other agonists and in cell-cell interactions with other cell types of the vascular wall, with blood cells and with cellular products. Consequently, a new requirement has arisen for cells in vitro that maintain the differentiated properties of their counterparts in vivo. The deleterious effects of trypsin and other proteolytic enzymes commonly used in cell culture on surface structures of endothelial cells such as enzymes, receptors and junctional proteins, as well as on extracellular layers such as the glycocalyx or "endothelial fuzz," have led to the development of methods that avoid use of proteolytic enzymes at both the isolation step and during subsequent subculture. This chapter describes traditional methods for isolating pulmonary endothelial cells but emphasizes newer approaches using mechanical harvest and scale-up using microcarriers. The new methods allow maintenance of long-term, large-scale cultures of cells that retain the full complement of surface properties and that maintain the cobblestone monolayer morphology and differentiated functional properties. Methods for identification of isolated cells are therefore also considered as methods for validation of cultures during their in vitro lifespan.

Elastin metabolism and chemistry: potential roles in lung development and structure.

Abstract: Elastic fibers are important for elasticity and extensibility of lung tissue. In the developing lung, elastic fibers appear in greatest numbers during the process or period of alveolarization . A variety of mesenchymal cells in lung appear responsible for elastin synthesis. Elastin is a novel protein both from the standpoint of its processing into elastic fibers and chemical properties. For example, elastin undergoes posttranslational modification before its assembly into fibers. These steps include limited proteolysis, hydroxylation of prolyl residues and the oxidative deamination of lysyl residues prior to their incorporation into the crosslinks that covalently bond together polypeptide chains of elastin. The crosslinking amino acids include lysinonorleucine , merodesmosine and desmosine isomers. A key enzyme that controls this process is lysyl oxidase. Lysyl oxidase is a copper metalloprotein whose activity is responsive to and modulated by environmental insults, nutrition deficiencies and the administration of various pharmacological agents. Regarding chemical properties, elastin is one of the most apolar proteins secreted by mammalian cells. Moreover, elastin is one of the most long-lived proteins secreted into the extracellular matrix. In relationship to its processing into elastic fibers and chemical properties, details related to major aspects of elastin metabolism as well as speculation on its potential as a factor in lung development and disease are discussed.

Intermediary Metabolism of the Lung

Abstract: The lung is a metabolically active organ that is engaged in secretion, clearance and other maintenance functions that require reducing potential, energy and substrates for biosynthesis. These metabolic requirements are met in part through uptake and catabolism of glucose which represents the major fuel utilized by lung tissues. Gluconeogenesis does not occur, and glycogen stores are limited so that the lung depends on the circulation for its glucose requirement. Other substrates can be metabolized by lung and contribute to the metabolic pool although their role has been less thoroughly studied. Glucose is catabolized in the lung by cytoplasmic and mitochondrial pathways that are responsive to regulatory mechanisms as in other tissues. Activity of the pentose cycle pathway of glucose catabolism is relatively high and generates the NADPH required for biosynthesis of lipid, detoxification reactions, and protection against oxidant stress. The ATP content of the lung is maintained by oxidative metabolism at levels comparable to other metabolically active organs. Alterations in lung intermediary metabolism may depress amine clearance, alter lung permeability, and influence the lung response to oxidant stress.

Chelation of cadmium.

Abstract: The toxicity of cadmium is determined by chelation reactions: in vivo, Cd2+ exists exclusively in coordination complexes with biological ligands, or with administered chelating agents. The Cd2+ ion has some soft character, but it is not a typical soft ion. It has a high degree of polarizability, and its complexes with soft ligands have predominantly covalent bond characteristics. Cd2+ forms the most stable complexes with soft donor atoms (S much greater than N greater than 0). The coordination stereochemistry of Cd2+ is unusually varied, including coordination numbers from 2 to 8. Even though the Cd2+ ion is a d10 ion, disturbed coordination geometries are often seen. Generally, the stability of complexes increases with the number of coordination groups contributed by the ligand; consequently, complexes of Cd2+ with polydentate ligands containing SH groups are very stable. Cd2+ in metallothionein (MT) is coordinated with 4 thiolate groups, and the log stability constant is estimated to 25.5. Complexes between Cd2+ and low molecular weight monodentate or bidentate ligands, e.g., free amino acids (LMW-Cd), seem to exist very briefly, and Cd2+ is rapidly bound to high molecular weight proteins, mainly serum albumin. These complexes (HMW-Cd) are rapidly scavenged from blood, mainly by the liver, and Cd2+ is redistributed to MT. After about 1 day the Cd-MT complex (MT-Cd) almost exclusively accounts for the total retained dose of Cd2+, independent of the route of exposure. MT-Cd is slowly transferred to and accumulated in kidney cortex. The acute toxicity and interorgan distribution of parenterally administered Cd2+ are strongly influenced by preceding MT induction, or decreased capacity for MT synthesis; however, the gastrointestinal (GI) uptake of Cd2+ seems unaffected by preceding MT induction resulting in considerable capacity for Cd2+ chelation in intestinal mucosa, and this finding indicates that endogenous MT is not involved in Cd2+ absorption. The toxicity of parenterally administered Cd2+ is strongly enhanced when administered as complexes with NTA or STPP , but it is much decreased when administered as a complex with EDTA. In chronic oral exposure the toxicity and GI uptake of Cd2+ is not changed when Cd2+ is administered as a complex with the detergent formula chelating agents NTA, EDTA and STPP . The uptake of Cd2+ from ligated intestine in vivo was not affected by administration of Cd2+ as complexes with CYS or GSH, but significantly reduced by complexation with EDTA or BAL. The acute toxicity of orally administered Cd2+ is reduced when Cd2+ is administered as a complex with EDTA.(ABSTRACT TRUNCATED AT 400 WORDS)

Developmental toxicity of four glycol ethers applied cutaneously to rats.

Abstract: Previous NIOSH studies demonstrated the embryo- and fetotoxicity and teratogenicity of ethylene glycol monoethyl ether (EGEE) applied to the shaved skin of pregnant rats. In the present study ethylene glycol monoethyl ether acetate (EGEEA), ethylene glycol monobutyl ether (EGBE), and diethylene glycol monoethyl ether (diEGEE) were tested in the same experimental model, using distilled water as the negative control and EGEE as a positive control. Water or undiluted glycols were applied four times daily on days 7 to 16 of gestation to the shaved interscapular skin with an automatic pipetter. Volumes of EGEE (0.25 mL), EGEEA (0.35 mL), and diEGEE (0.35 mL) were approximately equimolar (2.6 mmole per treatment). EGBE at 0.35 mL four times daily (approximately 2.7 mmole per treatment) killed 10 of 11 treated rats, and was subsequently tested at 0.12 mL (0.9 mmole) per treatment. EGEE- and EGEEA-treated rats showed a reduction in body weight relative to water controls that was associated with completely resorbed litters and significantly fewer live fetuses per litter. Fetal body weights were also significantly reduced in those groups. Visceral malformations and skeletal variations were significantly increased in EGEE and EGEEA groups over the negative control group. No embryotoxic, fetotoxic, or teratogenic effects were detected in the EGBE- or diEGEE-treated litters.

Review of glycol ether and glycol ether ester solvents used in the coating industry.

Abstract: Ethylene oxide-based glycol ether and glycol ether ester solvents have been used in the coatings industry for the past fifty years. Because of their excellent performance properties (evaporation ra...

Alterations in macrophage functions by environmental chemicals.

Abstract: The establishment of infectious diseases is rarely entirely attributed to a single entity, but instead is the result of a primary stress and one or more secondary factors that interfere with homeos

Results of testing fifteen glycol ethers in a short-term in vivo reproductive toxicity assay.

Abstract: Fifteen glycol ethers were investigated for their potential to cause adverse reproductive toxic effects using an in vivo mouse screening bioassay. Pregnant mice were orally dosed once per day on days 7 through 14 of gestation at concentrations causing 0 to 41% maternal mortality. Reproductive endpoints included pup survival in utero (percent of live litters/pregnant survivors), pup perinatal and postnatal survival (number of live pups per litter, number of dead pups per litter, and pup survival to 2.5 days of age), and pup body weight statistics (weight at birth and weight at 2.5 days of age). The study was conducted in two phases: a dose range-finding phase using nonpregnant female mice, and a definitive reproductive phase using time-mated mice. The range-finding phase sought to identify, for each chemical, the maternal LD10 as the target dose. However, based upon reproductive phase results, such an exact dose was impractical to achieve. Thus, a range from the LD5 to the LD20 was considered a sufficient challenge dose that would not affect results due to high mortality, i.e., greater than the LD20. Glycol ethers were assigned to groups having different priorities for further testing based upon whether a sufficient challenge dose was administered and the degree of effects recorded for each chemical.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of cytochrome P-450 and related enzymes in the pulmonary metabolism of xenobiotics

Abstract: The lung metabolizes a wide variety of xenobiotics and, in the process, forms products that may be more or less toxic than the parent compound. The consequence of metabolism, activation or detoxication, is a function of the nature of the substrate and of the characteristics and concentrations of the enzymes involved. As a result, the biotransformation of xenobiotics can lead to their excretion or to the formation of reactive products that produce deleterious effects by binding covalently to tissue macromolecules. Among the enzymes that metabolize xenobiotics, those associated with the cytochrome P-450-dependent monooxygenase system are probably the most important. The route by which a given substrate is metabolized in a tissue or cell is, to a great extent, determined by the types and concentrations of cytochrome P-450 isozymes present. We are just beginning to understand the distribution of these enzymes in lung and to appreciate the species and cellular differences that exist.

Metabolism and excretion of 2-ethoxyethanol in the adult male rat.

Abstract: The routes of 14C excretion following the administration of a single oral 230 mg/kg body weight dose of 2-ethoxyethanol [ethanol-1,2-14C] or 2-ethoxyethanol [ethoxy-1-14C] to male Sprague-Dawley ra...

Statistical association between cancer incidence and major-cause mortality and estimated residential exposure to air emissions from petroleum and chemical plants

Abstract: An ecologic study design was used to investigate the relationship between exposure to air emissions produced by the petroleum and chemical industries, and average annual cancer incidence and major cause mortality rates among whites in Contra Costa County, California. Estimates for the exposure to major industrial sources of sulfur dioxide, hydrocarbons and oxides of nitrogen were used to subdivide the county by level of exposure to petroleum refinery and chemical plant emissions. Cancer incidence and major cause mortality rates were then calculated for whites in each of the exposure areas. In both males and females, residential exposure to petroleum and chemical air emissions was associated with an increased incidence of cancer of the buccal cavity and pharynx. In males, age-adjusted incidence rates for cancers of the stomach, lung, prostate and kidney and urinary organs were also associated with petroleum and chemical plant air emission exposures. In both sexes, we found a strong positive association between degree of residential exposure and death rates from cardiovascular disease and cancer, and a less strong positive association between exposure and death rates from cerebrovascular disease. There was also a positive association in men for deaths from cirrhosis of the liver. Although these observed associations occurred across areas of similar socioeconomic and broad occupational class, confounding variables and the "ecologic fallacy" must be considered as possible explanations. In particular, the stronger findings in men suggest an occupational explanation of the cancer incidence trends, and the effect observed in cirrhosis mortality suggests that lifestyle variables such as alcohol consumption were not adequately controlled for. While the public health implications of our findings remain unclear, the evidence presented is sufficient to warrant follow-up studies based on individual data in which possible biases can be more readily controlled.

Inhibition of cellular antioxidants: a possible mechanism of toxic cell injury

Abstract: Cells that utilize molecular oxygen generate highly reactive oxygen-derived free radicals. Endogenous cellular oxidants inactivate oxidant free radicals and protect aerobic cells from oxidant injury. Glutathione, glutathione reductase, and superoxide dismutase are key components of this antioxidant defense. Inhibition of antioxidant components would be expected to result in cell injury. Using exposure to oxygen at high pressure to increase the level of oxidant free radicals, evidence is presented to support the hypothesis that inhibition of cellular antioxidants renders organisms more susceptible to oxygen toxicity. Diethyldithiocarbamate at doses of 250, 500 and 1000 mg/kg inhibited rat brain superoxide dismutase activity and shortened onset time to seizures in a dose-related manner in 4 ATA oxygen. Carmustine at doses of 12.5, 25 and 50 mg/kg inhibits glutathione reductase activity in rat brain in proportion to the dose. Time to onset of seizures of rats pretreated with carmustine prior to exposure to 4 ATA oxygen was shortened, and oxidized glutathione levels were increased in the cortex and subcortex. These data suggest that inhibition of antioxidant components results in organisms becoming more sensitive to oxygen toxicity. Compounds that inhibit cellular antioxidants may produce toxic cell injury by permitting intracellular oxidant free radicals to attack essential cell constituents.