Use of mode of action data to inform a dose-response assessment for bladder cancer following exposure to inorganic arsenic.

In the recent National Research Council report on conducting a dose-response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose-response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose-response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose-response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7-43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies.

Melanocytes and keratinocytes have distinct and shared responses to ultraviolet radiation and arsenic.

The rise of melanoma incidence in the United States is a growing public health concern. A limited number of epidemiology studies suggest an association between arsenic levels and melanoma risk. Arsenic acts as a co-carcinogen with ultraviolet radiation (UVR) for the development of squamous cell carcinoma and proposed mechanisms include generation of oxidative stress by arsenic and UVR and inhibition of UVR-induced DNA repair by arsenic. In this study, we investigate similarities and differences in response to arsenic and UVR in keratinocytes and melanocytes. Normal melanocytes are markedly more resistant to UVR-induced cytotoxicity than normal keratinocytes, but both cell types are equally sensitive to arsenite. Melanocytes were more resistant to arsenite and UVR stimulation of superoxide production than keratinocytes, but the concentration of arsenite necessary to inhibit the activity of the DNA repair protein poly(ADP-ribose)polymerase and enhance retention of UVR-induced DNA damage was essentially equivalent in both cell types. These findings suggest that although melanocytes are less sensitive than keratinocytes to initial UVR-mediated DNA damage, both of these important target cells in the skin share a mechanism related to arsenic inhibition of DNA repair. These findings suggest that concurrent chronic arsenic exposure could promote retention of unrepaired DNA damage in melanocytes and act as a co-carcinogen in melanoma.

Concentration- and time-dependent genomic changes in the mouse urinary bladder following exposure to arsenate in drinking water for up to 12 weeks.

Inorganic arsenic (As(i)) is a known human bladder carcinogen. The objective of this study was to examine the concentration dependence of the genomic response to As(i) in the urinary bladders of mice. C57BL/6J mice were exposed for 1 or 12 weeks to arsenate in drinking water at concentrations of 0.5, 2, 10, and 50 mg As/l. Urinary bladders were analyzed using gene expression microarrays. A consistent reversal was observed in the direction of gene expression change: from predominantly decreased expression at 1 week to predominantly increased expression at 12 weeks. These results are consistent with evidence from in vitro studies of an acute adaptive response that is suppressed on longer exposure due to downregulation of Fos. Pathways with the highest enrichment in gene expression changes were associated with epithelial-to-mesenchymal transition, inflammation, and proliferation. Benchmark dose (BMD) analysis determined that the lowest median BMD values for pathways were above 5 mg As/l, despite the fact that pathway enrichment was observed at the 0.5 mg As/l exposure concentration. This disparity may result from the nonmonotonic nature of the concentration-responses for the expression changes of a number of genes, as evidenced by the much fewer gene expression changes at 2 mg As/l compared with lower or higher concentrations. Pathway categories with concentration-related gene expression changes included cellular morphogenesis, inflammation, apoptosis/survival, cell cycle control, and DNA damage response. The results of this study provide evidence of a concentration-dependent transition in the mode of action for the subchronic effects of As(i) in mouse bladder cells in the vicinity of 2 mg As(i)/l.

An evaluation of surrogate chemical exposure measures and autism prevalence in Texas.

There is currently considerable discussion in the scientific community as well as within the general public concerning the role mercury (Hg) exposures may play in the apparent increased incidence of neurodevelopmental disorders (particularly autism) in children. Although the primary focus of this debate has focused on ethylmercury from vaccinations, linkage to other sources of Hg has been proposed. An ecologic association between 2001 Toxic Release Inventory (TRI; www.epa.gov/tri) data for Hg and 2000-2001 school district autism prevalence was previously reported in Texas. Evaluations using industrial release data as surrogate exposure measures may be problematic, particularly for chemicals like Hg that have complex environmental fates. To explore the robustness of TRI-based analyses of the Hg-autism hypothesis in Texas, a detailed analysis was undertaken examining the extent of the ecological relationship during multiple years and examining whether surrogate exposure measures would yield similar conclusions. Using multilevel Poisson regression analysis and data obtained from a number of publicly available databases, it was found that air Hg release data were significantly associated with autism prevalence in Texas school districts when considering data for 2001 and 2002 (2001: RR = 4.45, 95% CI = 1.60-12.36, 2002: RR = 2.70, 95% CI = 1.17-6.15). Significant associations were not found using data from 2003 to 2005. A significant association was not observed when considering air Hg data for 2000 or 2001 and school district autism prevalence data for 2005-2006 or 2006-2007, an analysis allowing for a 5-yr time period between presumed exposure and entry into the public school system (2000: RR = 1.03, 95% CI = 0.59-1.83, 2001: RR = 0.94, 95% CI = 0.59-1.47). Significant associations were not observed for any year nor for the time lagged analyses when censored autism counts were replaced by threes instead of zeros. An evaluation of TRI air emissions data for several other pollutants did not find significant associations except for nickel (RR = 1.71, 1.12-2.60), which has no history of being associated with neurodevelopmental disorders. An evaluation using downwind location from coal-fired power plants as the exposure surrogate variable also did not yield statistically significant results. The analysis suggests Hg emissions are not consistently associated with autism prevalence in Texas school districts. The lack of consistency across time may be the result of the influence of a more significant factor which remains unidentified. Alternatively, it may be that the significant association observed in 2001 and 2002 does not represent a true causal association.

Tissue distribution and urinary excretion of inorganic arsenic and its methylated metabolites in C57BL6 mice following subchronic exposure to arsenate in drinking water.

The relationship of exposure and tissue concentration of parent chemical and metabolites over prolonged exposure is a critical issue for chronic toxicities mediated by metabolite(s) rather than parent chemical alone. This is an issue for AsV because its trivalent metabolites have unique toxicities and relatively greater potency compared to their pentavalent counterparts for many endpoints. In this study, dose-dependency in tissue distribution and urinary excretion for inorganic arsenic and its methylated metabolites was assessed in female C57Bl/6 mice exposed to 0, 0.5, 2, 10 or 50 ppm arsenic (as arsenate, AsV) in their drinking water for 12 weeks. No adverse effects were observed and body weight gain did not differ significantly among groups. Urinary excretion of arsenite monomethylarsonous acid (MMA(III)), dimethylarsinous acid (DMA(III)), dimethylarsinic acid (DMAV), and trimethylarsine oxide (TMAO) increased linearly with dose, whereas AsV and monomethylarsonic acid (MMAV) excretion was non-linear with respect to dose. Total tissue arsenic accumulation was greatest in kidney > lung > urinary bladder >>> skin > blood > liver. Monomethyl arsenic (MMA, i.e. MMA(III)+MMAV) was the predominant metabolite in kidney, whereas dimethylarsenic (DMA, i.e., DMA(III)+DMAV) was the predominant metabolite in lung. Urinary bladder tissue had roughly equivalent levels of inorganic arsenic and dimethylarsenic, as did skin. These data indicate that pharmacokinetic models for arsenic metabolism and disposition need to include mechanisms for organ-specific accumulation of some arsenicals and that urinary metabolite profiles are not necessarily reflective of target tissue dosimetry.

Development of an occupational illness and injury surveillance database for the electric energy sector.

Currently available occupational injury and illness data for electric energy companies provide only overall summary rates. Specific information about types of injury or illnesses, rates by occupational or work environments, and injury costs and severity are generally not readily available. Relevant data such as personnel and claims information are frequently not integrated into a comprehensive health and safety surveillance system suitable for epidemiologic and health and safety research purposes. Epidemiological methods are valuable for identifying key risk factors for work-related injuries and illnesses and assessing their magnitude, as well establishing priorities for health and safety research. Application of such methods can result in long-term reductions in injury and illness rates and their attendant costs. Aggregation of relevant health and safety data across companies improves statistical power for the assessment of rare (yet costly) injuries or illness or specific at-risk subgroups within the electric energy sector. A pilot occupational injury and illness database has been developed that can incorporate and standardize data across a spectrum of companies of differing sizes and configurations. In illustrative data analyses, injury trends were summarized by company size, occupation, and demographic factors, among others. Trends observed in these illustrative analyses were consistent with results previously reported in the epidemiological literature, however, results are considered preliminary pending development of the full database. This study shows that development of a standardized surveillance occupational injury and illness database across companies with different database configurations is feasible. This database will ultimately provide a stable and accurate occupational health and safety assessment tool not currently available for this sector.

Coal fly ash- and copper smelter dust-induced modulation of ex vivo production of tumor necrosis factor-alpha by murine macrophages: effects of metals and overload.

The objective of this study was to assess the effect of two arsenic-containing particles, coal fly ash (FA) and copper smelter dust (CU), on lung integrity and on the ex vivo release of tumor necrosis factor alpha (TNF-alpha) by alveolar phagocytes. Particle effects were compared in nonoverload condition on the basis of a low but identical volume load and arsenic content intratracheally instilled in the mouse lung (273 nl/mouse and 186 ng arsenic/mouse; FAL and CUL groups). Other mice received 600 ng arsenic/mouse in amounts of particles leading to different volume loads (FAH and CUH groups: 880 and 273 nl/mouse, respectively). Animals were sacrificed at 1, 6, 30, or 120 d (FAL and CUL groups) or at 6 and 120 d posttreatment (FAH and CUH groups). Biochemical markers and inflammatory cell number and type were analyzed in bronchoalveolar lavage, ex vivo TNF-alpha production by alveolar phagocytes was assessed, and measurement of arsenic lung content and histopathological examinations were performed. Our results show that coal fly ash and copper smelter dust bear distinct inflammatory properties. At the end of the observation period (d 120), the high CU dose (CUH) produced a fibrotic reaction whereas the high dose of FA particles (FAH) generated a delayed and persistent lung inflammatory reaction associated with lymphoid noduli. Marked differences in TNF-alpha production were observed within the CU and FA groups. CU particles, conceivably through their metal content, decreased TNF-alpha production by alveolar phagocytes. Due to their low arsenic content, considerably higher FA particle doses needed to be administered to produce an inhibition of TNF-alpha production. Since high doses of FA (FAH) caused an overload condition, our results do not allow us to decide whether FA-mediated TNF-alpha reduction is due to the load administered or to the metallic content.

Airborne arsenic and urinary excretion of arsenic metabolites during boiler cleaning operations in a Slovak coal-fired power plant.

Little information is available on the relationship between occupational exposure to inorganic arsenic in coal fly ash and urinary excretion of arsenic metabolites. This study ws undertaken in a coal-fired power plant in Slovakia during a routine maintenance outage. Arsenic was measured in the breathing zone of workers during 5 consecutive workdays, and urine samples were obtained for analysis of arsenic metabolites--inorganic arsenic (Asi), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)--prior to the start of each shift. Results from a small number of cascade impactor air samples indicated that approximately 90% of total particle mass and arsenic was present in particle size fractions >/= 3.5 micron. The 8-hr time-weighted average (TWA) mean arsenic air concentration was 48.3 microg/m3 (range 0.17-375.2) and the mean sum of urinary arsenic (SigmaAs) metabolites was 16.9 microg As/g creatinine (range 2.6-50.8). For an 8-hr TWA of 10 microg/m3 arsenic from coal fly ash, the predicted mean concentration of the SigmaAs urinary metabolites was 13.2 microg As/G creatinine [95% confidence interval (CI), 10.1-16.3). Comparisons with previously published studies of exposure to arsenic trioxide vapors and dusts in copper smelters suggest that bioavailability of arsenic from airborne coal fly ash (as indicated by urinary excretion) is about one-third that seen in smelters and similar settings. Arsenic compound characteristics, matrix composition, and particle size distribution probably play major roles in determining actual uptake of airborne arsenic.

Reduction of the ex vivo production of tumor necrosis factor alpha by alveolar phagocytes after administration of coal fly ash and copper smelter dust.

We investigated the effect of intratracheally instilled coal fly ash (FA) and copper smelter dust (CU) on the lung integrity and on the ex vivo release of tumor necrosis factor alpha (TNF-alpha) by alveolar phagocytes. Groups of female NMRI mice received a single intratracheal administration of different particles normalized for the arsenic content (20 micrograms/kg body weight, i.e., 600 ng arsenic/mouse) and the particle load (100 mg/kg body weight, i.e., 3 mg/mouse). Mice received tungsten carbide (WC) alone (100 mg/kg), FA alone (100 mg/kg, i.e., 20 micrograms arsenic/kg), CU mixed with WC (CU, 13.6 mg/kg, i.e., 20 micrograms arsenic/kg; WC, 86.4 mg/kg) and Ca3(AsO4)2 mixed with WC (20 micrograms arsenic/kg; WC, 100 mg/kg). Animals were sacrificed at 1, 6, or 30 d posttreatment and analyzed by bronchoalveolar lavage for total protein (TP) content, inflammatory cell number and type, and TNF-alpha production. Additional mice were studied to evaluate particle retention by measuring total arsenic retention in the lung at appropriate times. Instillation of WC induced a mild and transient (d 1) inflammatory reaction characterized by an increase of TP and an influx of polymorphonuclear leukocytes in the alveolar compartment. Compared to WC, Ca3(AsO4)2 produced a significant increase of TP content in BALF. CU particles caused a severe but transient inflammatory reaction, while a persisting alveolitis (30 d) was observed after treatment with FA. Compared to control saline, a marked inhibition of TNF-alpha release was observed in response to LPS in all groups at d 1. Cytokine production was upregulated in WC- and Ca3(AsO4)1-treated animals after 6 and 30 d, respectively. However, a 90% inhibition of TNF-alpha production was still observed at d 30 after administration of CU and FA. Although arsenic was cleared from the lung tissue 6 d after Ca3(AsO4)2 administration, a significant fraction persisted (10-15% of the arsenic administered) in the lung of CU- and FA-treated mice at d 30. We hypothetize that suppression of TNF-alpha production is dependent upon the slow elimination of the particles and their metal content from the lung.

Effect of hepatic methyl donor status on urinary excretion and DNA damage in B6C3F1 mice treated with sodium arsenite.

This study evaluated the effect of hepatic methyl donor status on the ability of sodium arsenite (2.5, 5.0 and 10.0 mg/kg) administered by gavage once or on four consecutive days to induce DNA damage in male B6C3F1 mice. Maintenance on a choline-deficient (CD) diet prior to treatment resulted in mice with hepatic methyl donor deficiency (HMDD) and altered arsenical metabolism, as demonstrated by a decreased total urinary excretion of inorganic and organic arsenicals. The alkaline (pH > 13) Single Cell Gel (SCG) assay was used to evaluate for the induction of DNA damage (single strand breaks, alkali labile sites, DNA crosslinking) in blood leukocytes, liver parenchymal cells, and cells sampled from bladder, lung, and skin, while the bone marrow erythrocyte micronucleus (MN) assay was used to assess for the induction of chromosomal damage in bone marrow cells. Treatment with sodium arsenite once or four times induced a significant decrease in DNA migration (indicative of DNA crosslinking) in bladder and liver parenchymal cells of hepatic methyl donor sufficient (HMDS) mice, but in skin cells of HMDD mice. Both HMDD and HMDS mice exhibited a significant increase in the frequency of micronucleated polychromatic erythrocytes (MN-PCE) in bone marrow following four, but not following one, treatments. However, the positive response occurred at a lower dose for HMDS mice and, in these mice, bone marrow toxicity, as demonstrated by a significant reduction in the percentage of PCE, was present also. These results indicate that hepatic methyl donors deficiency significantly decreases the total urinary excretion of orally administered sodium arsenite and markedly modulates target organ arsenic-induced DNA damage, with an apparent shift from liver and bladder to skin.

Study of arsenic mutagenesis using the plasmid shuttle vector pZ189 propagated in DNA repair proficient human cells.

Arsenic is considered a human carcinogen and although it is non-mutagenic in bacterial or human cells, arsenic interacts synergistically with genotoxic agents in the production of mutations. To gain insight into the possible mechanisms of action of arsenic in mutagenesis we studied the effects of sodium arsenite exposure on UV mutagenesis using the pZ189 shuttle vector system in DNA repair proficient GM 637 human fibroblasts. The purpose of the study was to determine whether arsenic alone induces mutations in the supF gene and whether the combination of arsenic and UV irradiation leads to a yield of mutants greater than the sum of the arsenic or UV treatments alone. Treatment of fibroblasts for 72 h with 5.0 microM of sodium arsenite alone produced significant increases in the pZ189 mutant frequency; 1 and 2.5 microM arsenite were not mutagenic. UV irradiation (320 J/m2) increased the yield of mutants 3.5-fold above the background rate. When UV-irradiated plasmid was allowed to replicate in fibroblasts treated with 1, 2.5, or 5.0 microM arsenite, the yields of mutations were significantly greater (p < 0.01) than the yield expected if the effects of each treatment were simply additive. The greatest potentiation of UV-induced mutations (4.9-fold) was observed at 1 microM arsenite, a concentration that was neither mutagenic itself nor cytotoxic. Restriction digest and DNA sequencing analyses indicated that arsenite alone produces both large-scale rearrangements, frameshifts and base substitutions. Hotspots for deletions were observed to be associated with a previously reported deletion hotspot involving 5'-CpC and runs of cytosines. Base substitutions observed involved A:T-->T:A transversions. The results indicate that arsenite alone is mutagenic in human cells using the supF reporter gene. The pZ189 shuttle vector may provide a model to study the molecular nature of co-mutagenesis of arsenic and other environmental agents. Further characterization of arsenic's effects on DNA repair and mutational spectra may be useful in the development of molecular markers in studies of arsenic carcinogenesis in human populations.

Inhibition of poly(ADP-ribose) polymerase by arsenite.

Inorganic arsenic is considered a human carcinogen based principally on epidemiological evidence. Unlike most initiating chemicals, arsenic is inactive or extremely weak in its ability to directly induce gene mutations. Arsenite has been shown, however, to enhance mutagenicity when present with other agents such as UV radiation. Synergistic potentiation of chromosomal damage has been shown with co-treatment with DNA-crosslinking agents. Arsenite at low concentrations is known to be highly selective in reacting with closely spaced (vicinal) dithiol groups in proteins. Poly(ADP-ribose) polymerase (PARP) is known to contain such vicinal dithiol groups. Stimulation of PARP is an immediate response of eukaryotic cells to DNA strand breaks and has been implicated in DNA repair. The effect of treatment with sodium arsenite on PARP activity was assessed as follows: Molt-3 cells (a human T-cell lymphoma-derived cell line) in culture were treated for 24 h with concentrations of sodium arsenite ranging from 2.5 up to 25 microM. Speciation of inorganic arsenic and cell viability were determined. Cell cycle kinetics were measured by flow cytometry. Poly(ADP-ribose) synthesis was assayed using a palindromic decameric deoxynucleotide to stimulate enzyme activity. Results show that arsenite decreases PARP activity in a dose-dependent manner with an approximately 50% decrease in enzyme activity at 10 microM arsenite and 80% viability. The percent of cells in S-phase increases with increasing concentration of arsenite. These results provide further indication that arsenite may potentiate genetic damage through reaction with dithiols in DNA repair proteins such as PARP, perhaps resulting in interference with normal repair function.

'Spontaneous' genetic damage in man: evaluation of interindividual variability, relationship among markers of damage, and influence of nutritional status.

The 'spontaneous' frequency of genetic damage (normal background) and the possible relationship of this damage to nutritional variables in humans were investigated in 22 subjects using several indices of genetic damage. The subjects were chosen, out of 122 initially analyzed, for being at the extremes of the highest and lowest values of one index of genetic damage, the frequency of micronucleated erythrocytes in peripheral blood. This index reflects chromosomal damage and loss in bone marrow erythropoietic cells. The assay for micronuclei is convenient but is restricted to splenectomized individuals because the human spleen removes micronucleated cells. The initial 122 subjects were splenectomized, but all were normal and healthy at the time of this study and none had a previous history of neoplastic disease. Factors investigated were stability of micronucleus frequency as a function of time, correlations among multiple markers of genetic damage, and influence on damage indices of nutritional variables, including blood levels of folate, B12 and antioxidant vitamins. Among different individuals, the range of values was 10-fold or more in the erythrocyte micronucleus, glycophorin A, plasma ascorbate and urinary 8-hydroxydeoxyguanosine (oxo8dG) assays, was approximately 6-fold in the lymphocyte micronucleus assay, and was 2-fold in the lymphocyte sister chromatid exchange (SCE) assay. Red blood cell folate and plasma folate, B12 and alpha-tocopherol values varied by up to 10-fold among individuals. Micronucleus frequencies in erythrocytes and peripheral blood lymphocytes ranged from < 0.3 to 16.9/1000 in mature red blood cells, < 1 to 33/1000 in reticulocytes, and 2.5 to 15/1000 in binucleate lymphocytes. Frequencies of glycophorin A variant erythrocytes ranged from 5.6 to 77.3 x 10(6) N/0 cells and 3.2 to 16.2 x 10(6) N/N cells, and oxo8dG excretion varied from 32 to 397 pmol/kg/day. Although a wide range of values was observed in each genetic endpoint, the extreme values for various endpoints of genetic damage were not observed in the same individuals. The frequency of micronucleated erythrocytes varied over time within individuals and indicated that individuals with the highest levels of damage exhibit greater variability than those with lower levels. In some subjects, frequencies of micronucleated erythrocytes changed dramatically over an interval of 2-3 years: four subjects with initial micronucleated reticulocyte frequencies of 20.4, 5.9, 6.4 and 33/1000 changed to 2.5, 20.5, 18.5 and 12/1000, respectively. Among more than 150 individuals we have studied, including the 64 individuals studied by Everson et al. [(1988) J. Natl. Cancer Inst., 80, 525-529] and Smith et al. [(1990) Cancer Res., 50, 5049-5054], the seven individuals with the highest observed frequencies of micronucleated erythrocytes all had exceptionally low values of plasma folate, red cell folate, or plasma B12, suggesting that folate and B12 status are the major determinants of the types of damage that lead to spontaneous micronucleus formation in erythrocytic cells.

An investigation of multiple biomarkers among workers exposed to styrene and styrene-7,8-oxide.

Investigations of cancer and cytogenetic damage among reinforced-plastics workers have produced contradictory results. In all studies, the focus has been on styrene rather than the carcinogen, styrene-7,8-oxide (SO), traces of which are generated during the manufacturing process. Because styrene is present at very high levels and is metabolized almost exclusively through SO, coexposures to SO have been discounted. This study investigated the relative contributions of airborne styrene and SO and of smoking toward several SO-specific biomarkers (DNA and albumin adducts) and sister chromatid exchanges in the blood of 48 reinforced-plastics workers. Among individual subjects, albumin and DNA adducts as well as sister chromatid exchanges were significantly correlated with styrene exposure. However, among the 20 subjects with measurements to both styrene and SO, albumin adducts were significantly correlated with exposure to SO but not to styrene. Finally, among the 10 job groups, surprisingly strong correlations (0.709 < or = r < or = 0.966) were found between all SO biomarkers and exposure to SO but not to styrene. Calculations suggest that SO was about 2000 times more effective than styrene in producing SO biomarkers. After accounting for the disparate exposures to the two chemicals, a typical worker received 71% of the systemic dose of SO via inhalation; nonetheless, 5 of the 20 subjects received the majority of the SO dose from styrene. Cigarette smoking increased levels of SO-albumin and SO-DNA adducts, suggesting that SO was a constituent of tobacco smoke. We conclude that inhalation of SO should be considered in any interventions to reduce health risks.

The relationship between environmental monitoring and biological markers in exposure assessment.

The poor quality of traditional assessments of exposure has encouraged epidemiologists to explore biological monitoring in studies of chronic diseases. Yet, despite theoretical advantages, biomarkers have not been widely used in such applications. This article compares the general utility of a biomarker with that of the measurement of exposure per se. Points are illustrated with a longitudinal study of boat workers in which levels of styrene in the breathing zone and in exhaled air were compared to sister chromatid exchanges (SCEs) in peripheral lymphocytes. First, the linear relationship is explored between personal exposure and the levels of a biomarker in the cohort. A good fit to the straight-line relationship reflected by a correlation coefficient which is close to 1, such as observed with styrene in exhaled air (r2 = 0.83), suggests linear kinetics, that the appropriate route of exposure was measured by personal monitoring, small interindividual differences, adequate sample sizes, and a specific biomarker. However, a small correlation coefficient, as observed between SCEs and styrene exposure (r2 = 0.11), indicates that either kinetics were nonlinear or that more complex issues were involved with one or more of these factors. Second, environmental and biologic measurements are compared for use as independent variables in establishing a straight-line relationship between exposure and the health effect. If the ratio of the within-person to the between-person components of variance of the independent variable is large, then significant attenuation results when estimating the slope of the line.(ABSTRACT TRUNCATED AT 250 WORDS)

Lung retention and bioavailability of arsenic after single intratracheal administration of sodium arsenite, sodium arsenate, fly ash and copper smelter dust in the hamster.

Arsenic is present in airborne particulate material released by coal-fired power plants and non-ferrous metal smelters. We have assessed whether the physico-chemical properties of arsenic in such particles play a role in its lung retention and uptake by the body. Female hamsters were given a single intratracheal instillation of fly ash or copper smelter dust suspensions (at doses of 50 or 100 µg As kg(-1)) or identical amounts of soluble tri- and pentavalent arsenic, in the presence or absence of an inert dust material (tungsten carbide). The concentration of the element was measured in a 24 hour urine sample collected on the 1st, 2nd and 6th day after treatment and arsenic remaining in lung tissue was determined at the end of the same time periods. Both lung retention and urinary As excretion indicate a prolonged contact of the lung tissue with particulate As in contrast to soluble As salts. In addition to the effect of solubility described here, more research is needed to determine the effect of particle size and lung loading on retention, as well as the potential differences in the lung inflammatory response using arsenic-rich particulates from various sources.

Sister-chromatid exchanges in lymphocytes are increased in relation to longitudinally measured occupational exposure to low concentrations of styrene.

A longitudinal investigation of styrene exposure was conducted among 48 workers employed at a reinforced plastic boat manufacturing facility. 8-h time-weighted average (TWA) exposures to styrene and concentrations of styrene in the breath were determined for each individual on 7 randomly chosen days during 1 year. Peripheral blood lymphocytes from each subject were analyzed for sister chromatid exchanges (SCEs) 2 times and micronuclei (MN) 4 times during this period. Individual mean SCEs ranged from 4.7 to 9.5 SCEs per cell with a population mean of 6.4 +/- 0.2 SCEs per cell. SCEs were found to be significantly increased with an overall observed increase of 11.7% related to increasing exposure to styrene (mean air concentration 64.2 mg/m3 +/- 71.5; range 0.88-235 mg/m3) and with cigarette smoking. Examination of the relative contribution of each variable to regression of SCEs showed that smoking contributed about 62% and styrene exposure contributed about 25% of the total variability. Intra-individual lymphocyte MN frequencies did not vary significantly over time nor was a gradient toward increased MN observed with styrene exposure. However, significant inter-individual differences in MN frequencies were observed. Females had significantly higher MN frequencies than did males; MN were also increased with age. This study is highly unusual in that it illustrates the ability to separately quantify the relative contribution of each of two variables--smoking and styrene exposure--to an increase in SCEs in lymphocytes of an exposed human population.

Enhancement of chromosomal damage by arsenic: implications for mechanism.

Arsenic is a naturally occurring metalloid that has been associated with increased incidence of human cancer in certain highly exposed populations. Arsenic is released to the environment by natural means such as solubilization from geologic formations into water supplies. It is also released to occupational and community environments by such activities as nonferrous ore smelting and combustion of fuels containing arsenic. Several lines of evidence indicate that arsenic acts indirectly with other agents to ultimately enhance specific genotoxic effects that may lead to carcinogenesis. Work described here indicates that arsenite specifically potentiates chromosomal aberrations induced by a DNA crosslinking agent, 1,3-butadiene diepoxide, but does not effect the induction of sister chromatid exchanges under the same treatment conditions. It is proposed that the specific co-clastogenic effects of arsenite seen here may be mediated by its interference with DNA repair activities. Further understanding of the mechanism by which arsenic interacts with other environmental agents will result in more accurate estimates of risk from exposure to arsenic.

Specificity of arsenite in potentiating cytogenetic damage induced by the DNA crosslinking agent diepoxybutane.

In the present study, the induction of sister chromatid exchanges (SCEs) and chromosomal aberrations were measured in normal human lymphocytes treated with low concentrations of arsenite alone (0.5-2.0 microM) and arsenite in combination with the potent DNA crosslinking agent diepoxybutane (DEB). Experiments were carried out with lymphocytes from blood donors with different sensitivities to SCE induction by DEB. Arsenite, beginning at concentrations as low as 1 microM, increased SCE frequencies; chromosomal aberration frequencies were increased at 2 microM of arsenite. DEB treatments alone increased SCE frequencies and chromosomal aberrations. The yields of chromatid deletions and exchanges in lymphocytes exposed to both arsenite and DEB were markedly increased above the levels expected if the effects of the two agents had been simply additive. The frequencies of chromatid deletions were 4- to 8-fold greater than expected and chromatid exchanges were increased 7- to 40-fold. Chromatid exchanges detected in cells treated with arsenite and DEB were predominately incomplete exchanges. The most dramatic increases in chromatid aberrations were observed in lymphocytes from an individual sensitive to SCE induction by DEB, indicating that individuals may vary in their sensitivity to the co-clastogenic effects of arsenite. At concentrations that dramatically affect aberrations, arsenite had no effect on the induction of SCEs by DEB. These studies suggest a specific interaction of arsenite with the induction or repair of DNA damage produced by DEB that leads to chromosomal aberrations but not to SCEs. Based on the selective chemical reactivity of low concentrations of arsenite with proteins containing vicinal dithiols and the occurrence of these groups within DNA repair proteins, it is proposed that the specific co-clastogenic effects of arsenite may be mediated by its interference with DNA repair activities.