Showing papers in "Environmental Health Perspectives in 1989"

Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: considerations for a congener-specific analysis.

Abstract: Polychlorinated biphenyls (PCBs) as environmental contaminants often cannot be adequately described by reference to Aroclors or to total PCBs. Although there are 209 possible PCB configurations (congeners), perhaps half that number account for nearly all of the environmental contamination attributable to PCBs. Still fewer congeners are both prevalent and either demonstrably or potentially toxic. If potential toxicity, environmental prevalence, and relative abundance in animal tissues are used as criteria, the number of environmentally threatening PCB congeners reduces to about thirty-six. Twenty-five of these account for 50 to 75% of total PCBs in tissue samples of fish, invertebrates, birds, and mammals. A few PCB congeners that are sterically similar to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) are directly toxic. Other PCB congeners, as well as those that are directly toxic, may also be involved in toxicity indirectly by stimulating the production of (inducing) bioactivating enzyme systems. The most consequential of these have the ability to induce aryl hydrocarbon metabolizing mixed-function oxidases (MFOs). A result can be an increased capacity for bioactivation of otherwise nontoxic foreign compounds such as certain polynuclear aromatic hydrocarbons (PAH) to cytotoxic or genotoxic metabolites. The effectiveness of specific PCB congeners as inducers of different types of cytochrome P-450-dependent MFO systems is determined by their stereochemistry. Although MFO induction is not a proximate cause, it is a strong correlate of certain kinds of toxicities. Structural patterns can thus be used to discriminate among PCB congeners on the basis of toxic potential, if not entirely on toxicity per se. Congeners that demonstrate 3-methylcholanthrene-type (3-MC-type) and mixed-type MFO induction have the greatest toxic potential. These congeners most closely resemble 2,3,7,8-TCDD in their structures and in their toxic effects. The larger group of phenobarbital-type (PB-type) inducers have considerably less potential for contributing to toxic effects. Weak inducers and noninducing congeners have the least potential for toxicity. Using the rationale described in this paper, we assigned the most evironmentally threatening PCB congeners to four groups. Congeners assigned to Group 1 are considered most likely to contribute to adverse biological effects attributable to PCBs in an environmental sample. Group 1A contains the three most potent (pure 3-MC-type inducer) congeners, IUPAC numbers 77, 126, and 169. Six congeners, numbers 105, 118, 128, 138, 156, and 170, are assigned to Group 1B. These congeners are mixed-type inducers that have been reported frequently in environmental samples.(ABSTRACT TRUNCATED AT 400 WORDS)

Adsorption of organic chemicals in soils.

Abstract: This paper presents a review on adsorption of organic chemicals on soils sediments and their constituents. The first part of this review deals with adsorption from gas and liquid phases and gives a discussion on the physical meaning of the shape of adsorption isotherms. Results show that no general rules can be proposed to describe univocally the relation between the shape of isotherms and the nature of adsorbate-adsorbent system. Kinetics of adsorption is discussed through the description of various models. Theoretical developments exist both for the thermodynamics and the kinetics of adsorption, but there is a strong need for experimental results. Possible adsorption mechanisms are ion exchange, interaction with metallic cations, hydrogen bonds, charge transfers, and London-van der Waals dispersion forces/hydrophobic effect. However, direct proofs of a given mechanism are rare. Several factors influence adsorption behavior. Electronic structure of adsorbed molecules, properties of adsorbents, and characteristics of the liquid phase are discussed in relation to adsorption. Such properties as water solubility, organic carbon content of adsorbing materials, and the composition of the liquid phase are particularly important. Evaluation of adsorption can be obtained through either laboratory measurements or use of several correlations. Adsorption measurements must be interpreted, taking into account treatment of adsorbent materials, experimental conditions, and secondary phenomena such as degradations. Correlations between adsorption coefficients and water-octanol partition coefficient or water solubility are numerous. They may be useful tools for prediction purposes. Relations with transport, bioavailability, and degradation are described.

Regulation of the differentiation of PC12 pheochromocytoma cells.

Abstract: The PC12 clone, developed from a pheochromocytoma tumor of the rat adrenal medulla, has become a premiere model for the study of neuronal differentiation. When treated in culture with nanomolar concentrations of nerve growth factor, PC12 cells stop dividing, elaborate processes, become electrically excitable, and will make synapses with appropriate muscle cells in culture. The changes induced by nerve growth factor lead to cells that, by any number of criteria, resemble mature sympathetic neurons. These changes are accompanied by a series of biochemical alterations occurring in the membrane, the cytoplasm, and the nucleus of the cell. Some of these events are independent of changes in transcription, while others clearly involve changes in gene expression. A number of the alterations seen in the cells involve increases or decreases in the phosphorylation of key cellular proteins. The information available thus far allows the construction of a hypothesis regarding the biochemical basis of PC12 differentiation.

Major Sources of Benzene Exposure

Abstract: Data from EPA's TEAM Study allow us to identify the major sources of exposure to benzene for much of the U.S. population. These sources turn out to be quite different from what had previously been considered the important sources. The most important source of exposure for 50 million smokers is the mainstream smoke from their cigarettes, which accounts for about half of the total population burden of exposure to benzene. Another 20% of nationwide exposure is contributed by various personal activities, such as driving and using attached garages. (Emissions from consumer products, building materials, paints, and adhesives may also be important, although data are largely lacking.) The traditional sources of atmospheric emissions (auto exhaust and industrial emissions) account for only about 20% of total exposure. Environmental tobacco smoke is an important source, accounting for about 5% of total nationwide exposure. A number of sources sometimes considered important, such as petroleum refining operations, petrochemical manufacturing, oil storage tanks, urban-industrial areas, service stations, certain foods, groundwater contamination, and underground gasoline leaks, appear to be unimportant on a nationwide basis.

Peroxidase-dependent metabolism of benzene's phenolic metabolites and its potential role in benzene toxicity and carcinogenicity

Abstract: The metabolism of two of benzene's phenolic metabolites, phenol and hydroquinone, by peroxidase enzymes has been studied in detail. Studies employing horseradish peroxidase and human myeloperoxidase have shown that in the presence of hydrogen peroxide phenol is converted to 4,4'-diphenoquinone and other covalent binding metabolites, whereas hydroquinone is converted solely to 1,4-benzoquinone. Surprisingly, phenol stimulates the latter conversion rather than inhibiting it, an effect that may play a role in the in vivo myelotoxicity of benzene. Indeed, repeated coadministration of phenol and hydroquinone to B6C3F1 mice results in a dramatic and significant decrease in bone marrow cellularity similar to that observed following benzene exposure. A mechanism of benzene-induced myelotoxicity is therefore proposed in which the accumulation and interaction of phenol and hydroquinone in the bone marrow and the peroxidase-dependent formation of 1,4-benzoquinone are important components. This mechanism may also be responsible, at least in part, for benzene's genotoxic effects, as 1,4-benzoquinone has been shown to damage DNA and is shown here to induce multiple micronuclei in human lymphocytes. Secondary activation of benzene's phenol metabolites in the bone marrow may therefore play an important role in benzene's myelotoxic and carcinogenic effects.

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Abstract: Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2; greater than 99.7% pure) were conducted in groups of 60 F344/N rats and 60 B6C3F1 mice of each sex for each of three exposure doses and vehicle controls. These composite studies on benzene were designed and conducted because of large production volume and widespread human exposure, because of the epidemiologic association with leukemia, and because previous experiments were considered inadequate or inconclusive for determining carcinogenicity in laboratory animals. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals. For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene in male F344/N rats, female F344/N rats, male B6C3F1 mice, and female B6C3F1 mice. In male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. In female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity.(ABSTRACT TRUNCATED AT 400 WORDS)

Human neuroblastoma cell lines as models for the in vitro study of neoplastic and neuronal cell differentiation.

Abstract: Neuroblastoma is a childhood solid tumor composed of primitive cells derived from precursors of the autonomic nervous system. This neoplasm has the highest rate of spontaneous regression of all cancer types and has been noted to undergo spontaneous and chemically induced differentiation into elements resembling mature nervous tissue. As such, neuroblastoma has been a prime model system for the study of neuronal differentiation and the process of cancer cell maturation. In this paper we review those agents that have been described to induce the differentiation of neuroblastoma, with an emphasis on the effects and possible mechanisms of action of a group of related compounds, the retinoids. With this model system and the availability of subclones that are both responsive and resistant to chemically induced differentiation, fundamental questions regarding the mechanisms and processes underlying cell maturation have become more amenable to in vitro study.

Molecular biology of keratinocyte differentiation.

Abstract: Epidermal keratinocytes (skin cells) are highly specialized epithelial cells designed to perform a very specific function, separation of the organism from its environment. To accomplish this the cells synthesize precursors and assemble them into two distinct structures, the cornified envelope and keratin intermediate filaments. The intermediate filaments are assembled from keratin monomers and the cornified envelope is assembled from a protein called involucrin and several other proteins. Expression of involucrin and the keratins genes are regulated as a function of the stage of keratinocyte differentiation and by various external agents such as calcium and vitamin A. To study the function of these structures and the regulation of precursor production we have cloned cDNA and genomic clones encoding involucrin and four of the keratin polypeptides. Retinoids profoundly alter the differentiation pattern of human epidermal keratinocytes, but the underlying biochemical basis of this change is not known. In this report we describe retinoid-promoted changes in keratin gene expression that may, in part, be responsible for the alteration in cellular phenotype in the presence of the vitamin. We also describe the novel structure of the human 40 kD keratin, a member of the keratin family that is retinoid responsive and is likely to be important during epidermal development. Finally, we describe the structure of the envelope precursor protein, involucrin, as determined from its DNA sequence and speculate on its role in cornified envelope formation.

Benzene, an experimental multipotential carcinogen: results of the long-term bioassays performed at the Bologna Institute of Oncology.

Abstract: In 1976, a systematic and integrated project of long-term carcinogenicity bioassays began at the Bentivoglio Experimental Unit of the Bologna Institute of Oncology. The Bologna experiments proved for the first time that benzene is an experimental carcinogen. These experiments demonstrated that benzene is carcinogenic when administered by ingestion and by inhalation and that it cause tumors in the various tested animal models (Sprague-Dawley rats, Wistar rats, Swiss mice, and RF/J mice). They also showed that benzene is a multipotential carcinogen, as it produces a variety of neoplasias in one or more of the tested animal models, including Zymbal gland carcinomas, carcinomas of the oral cavity, nasal cavities, skin, forestomach, and mammary glands, as well as angiosarcomas of the liver, hemolymphoreticular neoplasias, tumors of the lung, and possibly hepatomas. The Bologna experiments also indicated a clear-cut dose-response relationship in benzene carcinogenesis. This report presents the up-to-date results of the Bologna project. The need for more experimental research aimed at assessing the carcinogenic effects of low doses of benzene, of chemical mixtures containing benzene, and of benzene substitutes is emphasized. Also recommended are more comprehensive epidemiological investigations, extended to all types of malignancies, with particular regard to lung carcinomas.

Hematotoxicity and carcinogenicity of benzene.

Abstract: The hematotoxicity of benzene exposure has been well known for a century. Benzene causes leukocytopenia, thrombocytopenia, pancytopenia, etc. The clinical and hematologic picture of aplastic anemia resulting from benzene exposure is not different from classical aplastic anemia; in some cases, mild bilirubinemia, changes in osmotic fragility, increase in lactic dehydrogenase and fecal urobilinogen, and occasionally some neurological abnormalities are found. Electromicroscopic findings in some cases of aplastic anemia with benzene exposure were similar to those observed by light microscopy. Benzene hepatitis-aplastic anemia syndrome was observed in a technician with benzene exposure. Ten months after occurrence of hepatitis B, a severe aplastic anemia developed. The first epidemiologic study proving the leukemogenicity of benzene was performed between 1967 and 1973 to 1974 among shoe workers in Istanbul. The incidence of leukemia was 13.59 per 100,000, which is a significant increase over that of leukemia in the general population. Following the prohibition and discontinuation of the use of benzene in Istanbul, there was a striking decrease in the number of leukemic shoe workers in Istanbul. In 23.7% of our series, consisting of 59 leukemic patients with benzene exposure, there was a preceding pancytopenic period. Furthermore, a familial connection was found in 10.2% of them. The 89.8% of our series showed the findings of acute leukemia. The possible factors that may determine the types of leukemia in benzene toxicity are discussed. The possible role of benzene exposure is presented in the development of malignant lymphoma, multiple myeloma, and lung cancer.

Health effects during a smog episode in West Germany in 1985.

Abstract: In January 1985 a smog period occurred for 5 days in parts of West Germany, including the Rhur District. Mortality (24,000 death certificates), morbidity in hospitals (13,000 hospital admissions, 5400 outpatients, 1500 ambulance transports) and consultations in doctors' offices (1,250,000 contacts) were studied for a 6-week period including the smog episode and a time interval before and thereafter. The study region was the State of North Rhine-Westfalia (16 million inhabitants), but the analysis is restricted to the comparison of the polluted area and a control area (6 million inhabitants each). During the smog period, mortality and morbidity in hospitals increased in the polluted area, but there was no substantial increase in the control area. The increases were for the total number of deaths 8 vs. 2% (polluted area vs. control area), for hospital admissions 15 vs. 3%, for outpatients 12 vs. 5% and for deliveries by ambulance to hospitals 28% in the polluted area (not investigated in the control area). The effects were more pronounced for cardiovascular diseases than for respiratory diseases. The consultations in doctors' offices show a slight decrease (-2 vs. -4%). Regression analysis shows a moderate influence of temperature, but a strong influence of ambient air pollution. The maxima of the ambient concentrations are more important on the same day, whereas the influence of the daily averages is more pronounced after a delay of 2 days. The results are discussed considering other possible confounders such as indoor pollution and psychogenic influences of the alarm situation. In total, the study suggests moderate health effects due to increased air pollution during the smog episode.

Benzene and leukemia: an epidemiologic risk assessment.

Abstract: To assess quantitatively the association between benzene and leukemia, we evaluated the rate of mortality experienced by a cohort occupationally exposed to benzene. Using data from historical air sampling surveys, we estimated the daily benzene exposure for each member of the cohort. The expected number of leukemia deaths was calculated and compared to the actual number of leukemia deaths that occurred. The overall standardized mortality ratio (SMR) for leukemia was 337. Person-years at risk within the cohort were stratified by increasing levels of cumulative benzene exposure. The resulting SMRs increased from 109 to 322 to 1186 and to 6637 with respective increases in cumulative benzene exposure from less than 40 ppm-years to 40-199, 200-399, and greater than 400. The shape of the exposure-response relation was examined with a case-control analysis. Another analysis was performed to take into account an induction period for leukemia. All of the analyses demonstrated that a strongly positive exposure-response relationship exists between benzene and leukemia. Previous attempts to quantify this cohort's risk of developing leukemia were based on surrogates of exposure, such as duration of employment. Using actual air sampling data to estimate individual exposures represents a marked improvement over these previous attempts and emphasizes the importance of conducting industrial hygiene surveys and maintaining historical exposure records.

Multiple mechanisms for the carcinogenic effects of asbestos and other mineral fibers.

Abstract: Asbestos and other mineral fibers are carcinogenic to humans and animals but differ from many carcinogens in that they do not induce gene mutations. An understanding of these interesting human carcinogens, therefore, is an important problem in cancer research. Asbestos and other fibers induce predominantly two types of cancers: mesotheliomas and bronchogenic carcinomas. Fiber size is an important factor in the carcinogenic activity of these substances as has been shown for mesothelioma induction. For bronchogenic carcinomas, but not for mesotheliomas, a synergistic effect of asbestos exposure and cigarette smoke has been observed in humans. The mechanisms by which fibers alone versus fibers in concert with other carcinogens induce cancers are probably distinct. In addition to fiber dimensions, fiber durability and surface properties of fibers are important properties affecting carcinogenicity. Evidence exists that asbestos is a complete carcinogen, an initiator and a promoter. Multiple mechanisms must be operative to explain the diverse effects of mineral fibers. Although asbestos is inactive as a gene mutagen, there is now clear evidence that it induces chromosomal mutations (aneuploidy and aberrations) in a wide variety of mammalian cells including mesothelial cells. Asbestos also induces transformation of cells in culture including mesothelial cells and fibroblasts. A mechanism for cell transformation, which is dependent on fiber dimension, has been proposed. The fibers are phagocytized by the cells and accumulate in the perinuclear region of the cells. When the cell undergoes mitosis, the physical presence of the fibers interferes with chromosome segregation and results in anaphase abnormalities. The transformed cells show aneuploidy and other chromosome abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary of carcinogenic potency and positivity for 492 rodent carcinogens in the carcinogenic potency database.

Abstract: A tabulation of carcinogenic potency (TD50) by species for 492 chemicals that induce tumors in rats or mice is presented. With the use of the Carcinogenic Potency Database, experimental results are...

Interspecies extrapolation in carcinogenesis: prediction between rats and mice.

Abstract: Interspecies extrapolation in carcinogenesis is studied by evaluating prediction from rats to mice and from mice to rats. The Carcinogenic Potency Database, which includes 3500 cancer tests conducted in rats or mice on 955 compounds, is used for the analysis. About half of the chemicals tested for carcinogenicity are positive in at least one test, and this proportion is similar when rats and mice are considered separately. For 392 chemicals tested in both species, 76% of the rat carcinogens are positive in the mouse, and 70% of mouse carcinogens are positive in the rat. When compounds composed solely of chlorine, carbon, hydrogen, and, optionally, oxygen are excluded from the analysis, 75% of mouse carcinogens are positive in the rat. Overall concordance (the percentage positive in both species plus the percentage negative in both) is 76%. Three factors that affect prediction between rats and mice are discussed: chemical class, mutagenicity in the Salmonella assay, and the dose level at which a chemical is toxic. Prediction is more accurate for mutagens than non-mutagens and for substances that are toxic at low (versus only at high) doses. Species differences are not the result of failure in the bioassay to attain the maximum tolerated dose in the negative species or of more frequent testing in the positive species. An analysis of the predictive value of positivity for the 10 most common target sites indicates that most sites are good predictors of carcinogenicity at some site in the other species; the poorest predictors among these common sites are the rat urinary bladder and the mouse liver.

Growth control and differentiation in mammary epithelial cells.

Abstract: Growth and differentiation of the mammary gland are controlled by various hormones and other environmental factors. The role of hormones and growth factors in mammary development is discussed with regard to animal species, physiological stages, and the various experimental systems in vitro. In the female embryo, mammary morphogenesis is induced by the mesenchyme and is hormone independent, whereas androgens cause the partial necrosis of mammary epithelium in the male. Ductal growth during adolescence requires estrogen and prolactin or growth hormone. During pregnancy, progesterone participates in the development of the lobuloalveolar structure of the gland. After parturition, changes in the hormonal environment lead to production and secretion of milk. Proliferation and differentiation of mammary epithelium can be induced in culture systems. Insulin and epidermal growth factor (EGF) stimulate mammary cell proliferation in vitro. EGF is required for the optimal growth of the mammary gland during pregnancy. EGF also appears to play an important role in mammary tumorigenesis in certain mouse strains. Production of milk proteins can be induced in vitro by the synergistic interactions of prolactin, insulin, and glucocorticoids and is inhibited by EGF and progesterone. Complete or partial sequencing of several milk protein genes and comparative analysis have led to identification of a sequence of high homology and conservation in the 5' flanking region that is likely to be involved in the regulation of milk protein gene expression.

Evidence supporting a role for active oxygen species in asbestos-induced toxicity and lung disease.

Abstract: Asbestos is an important occupational and environmental toxicant that affects several cell types in the respiratory tract. In an effort to understand how asbestos causes cell injury and/or altered proliferation and differentiation of cells, this laboratory has focused on reactive oxygen species as mediators of asbestos-induced biological effects. A compendium of experimental results reported by this laboratory and others supports this hypothesis. For example, scavengers of reactive oxygen metabolites and iron chelators (i.e., desferroxamine) prevent cytotoxicity after addition of asbestos to a variety of cell lines and macrophages in vitro. DNA strand breakage associated with toxicity of crocidolite asbestos in C3H10T 1/2 cells also is ameliorated with use of desferroxamine. All types of asbestos cause lipid peroxidation in mammalian cells and artificial membranes, a phenomenon that can be prevented by removal of catalytic iron. Last, asbestos causes generation of active oxygen species after interaction with leukocytes or by reduction of oxygen on the surface of the fibers.

Modeling multiphase migration of organic chemicals in groundwater systems--a review and assessment.

Abstract: Over the past two decades, a number of models have been developed to describe the multiphase migration of organic chemicals in the subsurface. This paper presents the state-of-the-art with regard t...

Effects of inhalation of acidic compounds on pulmonary function in allergic adolescent subjects.

Abstract: There is concern about the human health effects of inhalation of acid compounds found in urban air pollution. It was the purpose of this study to investigate three of these acid compounds, sulfur dioxide (SO/sub 2/), sulfuric acid (H/sub 2/SO/sub 4/), and nitric acid (HNO/sub 3/) in a group of allergic adolescent subjects. Subjects were exposed during rest and moderate exercise to 0.7 mumole/m/sup 3/ (68 micrograms/m/sup 3/) H/sub 2/SO/sub 4/, 4.0 mumole/m/sup 3/ (0.1 ppm) SO/sub 2/, or 2.0 mumole/m/sup 3/ (0.05 ppm) HNO/sub 3/. Pulmonary functions (FEV1, total respiratory resistance, and maximal flow) were measured before and after exposure. Preliminary analysis based on nine subjects indicates that exposure to 0.7 mumole/m/sup 3/ H/sub 2/SO/sub 4/ alone and in combination with SO/sub 2/ caused significant changes in pulmonary function, whereas exposure to air or SO/sub 2/ alone did not. FEV1 decreased an average of 6% after exposure to H/sub 2/SO/sub 4/ alone and 4% when the aerosol was combined with SO/sub 2/. The FEV1 decrease was 2% after both air and SO/sub 2/ exposures. Total respiratory resistance (RT) increased 15% after the combined H/sub 2/SO/sub 4/ exposures, 12% after H/sub 2/SO/sub 4/ alone, and 7% after exposure to air.more » After exposures to HNO3 alone, FEV1 decreased by 4%, and RT increased by 23%. These results are preliminary; final conclusions must wait for completion of the study.« less

Hematotoxicity and Carcinogenicity of Inhaled Benzene

Abstract: CBA/Ca male mice have been exposed to benzene in air at 10, 25, 100, 300, 400, and 3000 ppm for variable intervals 6 hr/day, 5 days/week for up to 16 weeks. Two weeks of inhaling 10 ppm produced no...

The effect of dose, dose rate, route of administration, and species on tissue and blood levels of benzene metabolites.

Abstract: Studies were completed in F344/N rats and B6C3F1 mice to determine the effect of dose, dose rate, route of administration, and rodent species on formation of total and individual benzene metabolites. Oral doses of 50 mg/kg or higher saturated the capacity for benzene metabolism in both rats and mice, resulting in an increased proportion of the administered dose being exhaled as benzene. The saturating air concentration for benzene metabolism during 6-hr exposures was between 130 and 900 ppm. At the highest exposure concentration, rats exhaled approximately half of the internal dose retained at the end of the 6-hr exposure as benzene; mice exhaled only 15% as benzene. Mice were able to convert more of the inhaled benzene to metabolites than were rats. In addition, mice metabolized more of the benzene by pathways leading to the putative toxic metabolites, benzoquinone and muconaldehyde, than did rats. In both rats and mice, the effect of increasing dose, administered orally or by inhalation, was to increase the proportion of the total metabolites that were the products of detoxification pathways relative to the products of pathways leading to putative toxic metabolites. This indicates low-affinity, high-capacity pathways for detoxification and high-affinity, low-capacity pathways leading to putative toxic metabolites. If the results of rodent studies performed at high doses were used to assess the health risk at low-dose exposures to benzene, the toxicity of benzene would be underestimated.

A retrospective cohort study of leukemia and other cancers in benzene workers.

Abstract: A retrospective cohort study was carried out in 1982–1983 among 28,460 benzene-exposed workers (15,643 males, 12,817 females) from 233 factories and 28,257 control workers (16,621 males, 12,366 fem...

Multistage models for carcinogenesis.

Abstract: The multistage model is tested on several human and animal data sets. It fits in some cases but not in others. With human lung cancer data, there is a drop in risk for ex-smokers quite different fr...

Multiple activation pathways of benzene leading to products with varying genotoxic characteristics.

Abstract: Benzene and 13 potential metabolites were investigated for genotoxicity in Salmonella typhimurium and V79 Chinese hamster cells. In the presence of NADPH-fortified hepatic postmitochondrial fraction (S9 mix), benzene reverted his- S. typhimurium strains. The effect was strongest in strain TA1535. Among the potential metabolites, only the trans-1,2-dihydrodiol, in the presence of S9 mix, and the diol epoxides, in the presence and absence of S9 mix, proved mutagenic in this strain. The anti-diol epoxide was more potent than the syn-diastereomer. Both enantiomers of the anti-diastereomer showed similar activities. S9 mix did not appreciably affect the mutagenicity of the anti-diol epoxide. However, detoxification was observed when purified rat liver dihydrodiol dehydrogenase (EC 1.3.1.20) was used at concentrations comparable to that present in the liver. The (1S)-anti-diol epoxide was a much better substrate than the (1R)-enantiomer, as was true also for (1S)-versus (1R)-trans-1,2-dihydrodiol. The anti-diol epoxide reverted all six strains of S. typhimurium used and induced all four genotoxic effects studied in V79 cells (sister chromatid exchange greater than acquisition of 6-thioguanine resistance, acquisition of ouabain resistance, micronuclei). However, other potential benzene metabolites showed genotoxic effects in V79 cells, as well: sister chromatid exchange was induced by the syn-diol epoxide, 1,2,4-trihydroxybenzene, hydroquinone, catechol, and 1,2,3-trihydroxybenzene. Elevated frequencies of micronucleated cells were observed after treatment with hydroquinone, 1,2,4-trihydroxybenzene, catechol, phenol, 1,2,3-trihydroxybenzene, and quinone. Mutations to 6-thioguanine resistance were induced by quinone, hydroquinone, 1,2,4-trihydroxybenzene, catechol, and the trans-1,2-dihydrodiol.(ABSTRACT TRUNCATED AT 250 WORDS)

10T1/2 cells: an in vitro model for molecular genetic analysis of mesodermal determination and differentiation.

Abstract: Progress has been made in understanding the molecular mechanisms that regulate cell type-specific gene expression during the terminal differentiation of cells into specialized tissue types. These studies have concentrated largely on defining the cis elements and trans-acting factors responsible for the transcription of differentiation-specific genes. Valuable as these investigations have been, they have not been able to place differentiation into the larger context of development, specifically into the context of the earlier developmental process of cell determination, when embryonic stem cell lineages are formed and the genetic regulatory programs for cell type-specific gene activation and expression are acquired by stem cells. The clonal mouse embryo cell line, C3H/10T1/2, clone 8 (10T1/2) provides a unique opportunity to examine the molecular genetic regulation of both the developmental determination of vertebrate stem cell lineages and their subsequent differentiation. 10T1/2 is an apparently multipotential cell line that can be converted by 5-azacytidine into three mesodermal stem cell lineages. These determined proliferative stem cells are stable in culture and retain their ability to differentiate in mitogen-depleted medium. The most significant discovery has been that 10T1/2 lineage determination is under simple genetic control and that the regulatory genes that mediate the formation of myogenic cell lineages, and likely the chondrogenic and adipogenic lineages, can be demonstrated and studied by genomic DNA and cDNA transfection approaches. This paper is a description of the remarkable properties and genetic behaviors of the 10T1/2 cells and a discussion of the insights that future studies of this cell may provide.

Studies of acid aerosols in six cities and in a new multi-city investigation: design issues.

Abstract: Techniques for measuring acid aerosols in the ambient environment have been developed only recently. As part of the on-going Harvard Study on the Health Effects of Sulfur Dioxide and Respirable Particulates, we have developed monitoring equipment for acidic particles that can be used in multiple field settings. Preliminary data suggest that these strong acid aerosol measurements may correlate with respiratory symptoms more closely than similar measurements of particulate matter less than 15 microns in size. These results have led to the beginning of a U.S.-Canadian cooperative study to assess the chronic effects of acid aerosols on the health of North American children. Communities are being selected on the basis of anticipated levels of H2SO4 in ambient air along with predicted levels of ozone and nitrates. Each community will undergo a 1-year period of every other day, 24-hr monitoring with newly developed monitoring equipment that will allow for quantification of H+ ion concentrations, as well as for specific measures of ozone and acid fractions. At the end of the 1-year period, while measurements are still being made, approximately 600 children aged 7 to 11 in each of up to 24 communities will be assessed with standardized questionnaires completed by parents, and pulmonary function will be measured in the children while in school. By estimating chronic exposure from the year-long measurement of acid aerosols and consideration of specific criteria for selecting communities to study, we hope to minimize potential confounding to allow us to assess the chronic impact of strong acid in the atmosphere on the respiratory health of these children.

Studies on the mechanism of benzene toxicity.

Abstract: Using the 59Fe uptake method of Lee et al. it was shown that erythropoiesis in female mice was inhibited following IP administration of benzene, hydroquinone, p-benzoquinone, and muconaldehyde. Toluene protected against the effects of benzene. Coadministration of phenol plus either hydroquinone or catechol resulted in greatly increased toxicity. The combination of metabolites most effective in reducing iron uptake was hydroquinone plus muconaldehyde. We have also shown that treating animals with benzene leads to the formation of adducts of bone marrow DNA as measured by the 32P-postlabeling technique.

The Ontario Air Pollution Study: identification of the causative agent.

Abstract: Previously published data from the Ontario Air Pollution study are reviewed. It has been shown that there is a consistent association in summer between hospital admissions for respiratory disease in Southern Ontario, and daily levels of SO4, O3, and temperature. No association exists for a group nonrespiratory conditions. Multiple regression analyses are presented that show all environmental variables account for 5.6% of the variability in respiratory admissions and that if temperature is forced into the analysis first, it accounts for 0.89% of the variability only. Distribution plots of standardized residuals are presented. In June of 1983, there were an exceptional number of ozone episodes (defined as occasions when ozone was greater than 82 ppb for 3 or more hours in a calendar day) in this region. A separate analysis of hospital admissions for acute respiratory diseases for the month of June for several years shows no demonstrable excess in June of 1983; previously regional analyses have indicated that ozone is associated with increased levels in July and August over a 9-year period. It has also been found that daily SO4 data collected at one monitoring site in the center of the region are not correlated with respiratory admissions, whereas the SO4 values collected every sixth day, on different days of the week, at 17 stations in the region had the highest correlation with respiratory admissions.(ABSTRACT TRUNCATED AT 250 WORDS)

Reexamination of London, England, mortality in relation to exposure to acidic aerosols during 1963-1972 winters.

Abstract: Air pollution epidemiology since the 1950s has been able to demonstrate that increases in daily mortality in London, England, were associated with elevated concentrations of index air pollutants, i.e., British Smoke (BS) and sulfur dioxide (SO2). In this work, we reanalyze that portion of the 1958-1972 winter mortality-pollution record for which daily direct acid aerosol measurements were made at a central site in London (St. Bartholomew's Medical College). The purposes of these exploratory analyses are to examine the dataset for indications of a relationship between acid aerosol pollution and human mortality and to compare any noted associations with those for other pollution variables. It is found that the log of acid aerosol concentrations is more strongly associated with raw total mortality in bivariate analyses than is BS or SO2, despite the fact that acid data are available from only one central site (versus seven disperse sites for BS and SO2). The logarithmic nature of the exposure side of the H2SO4-mortality relationship implies a saturation model of pollution effects, possibly due to multiday pollution harvesting influences on a susceptible subpopulation. Moreover, mortality-pollution cross-correlation analyses indicate that mortality effects usually follow pollution in time, supporting a causal relationship between the two. The apparent advantage of H2SO4 over BS in predicting total raw mortality is consistent with the hypothesis that it is the portion of particulate mass of greater health significance and may also allow the development of London mortality results which are more easily transferable to other environments than is the case for existing BS results.

Furnace-generated acid aerosols: speciation and pulmonary effects.

Abstract: Guinea pigs were exposed to ultrafine aerosols (less than 0.1 micron) of zinc oxide with a surface layer of sulfuric acid. These acid-coated aerosols are typical of primary emissions from smelters and coal combustors. Repeated daily 3-hr exposures for 5 days produce decrements in lung volumes and pulmonary diffusing capacity and elevations of lung weight/body weight ratio, protein, and number of neutrophils in pulmonary lavage fluid at concentrations of 20 micrograms/m3. A single 1-hr exposure to 20 micrograms/m3 causes increased bronchial reactivity. Higher concentrations of conventionally generated sulfuric acid mist are required to produce responses of similar magnitude.