Dermal exposure and urinary 1-hydroxypyrene among asphalt roofing workers.

The primary objective of this study was to identify significant determinants of dermal exposure to polycyclic aromatic compounds (PACs) among asphalt roofing workers and use urinary 1-hydroxyprene (1-OHP) measurements to evaluate the effect of dermal exposure on total absorbed dose. The study population included 26 asphalt roofing workers who performed three primary tasks: tearing off old roofs (tear-off), putting down new roofs (put-down), and operating the kettle at ground level (kettle). During multiple consecutive work shifts (90 workerdays), dermal patch samples were collected from the underside of each worker's wrists and were analyzed for PACs, pyrene, and benzo(a)pyrene (BAP). During the same work week, urine samples were collected at pre-shift, post-shift, and bedtime each day and were analyzed for 1-OHP (205 urine samples). Linear mixed effects models were used to evaluate the dermal measurements for the purpose of identifying important determinants of exposure, and to evaluate urinary 1-OHP measurements for the purpose of identifying important determinants of total absorbed dose. Dermal exposures to PAC, pyrene, and BAP were found to vary significantly by roofing task (tear-off > put-down > kettle) and by the presence of an old coal tar pitch roof (pitch > no pitch). For each of the three analytes, the adjusted mean dermal exposures associated with tear-off (812 ng PAC/cm2, 14.9 ng pyrene/cm2, 4.5 ng BAP/cm2) were approximately four times higher than exposures associated with operating the kettle (181 ng PAC/cm2, 4.1 ng pyrene/cm2, 1.1 ng BAP/cm2). Exposure to coal tar pitch was associated with a 6-fold increase in PAC exposure (p = 0.0005), an 8-fold increase in pyrene exposure (p < 0.0001), and a 35-fold increase in BAP exposure (p < 0.0001). Similarly, urinary 1-OHP levels were found to be significantly higher on days when an old pitch roof was removed, accounting for a 3.7-fold difference at pre-shift (p = 0.01), a 5.0-fold difference at post-shift (p = 0.004), and a 7.2-fold difference at bedtime (p = 0.002). The pyrene measurements obtained during the work shift were found to be strongly correlated with urinary 1-OHP measurements obtained at the end of that shift (r = 0.8, p < 0.001) as well as at bedtime (r = 0.7, p < 0.001). Ultimately, the results of a distributed lag model indicated that dermal exposure during the preceding 40 hours had a statistically significant effect on urinary 1-OHP. The presence of coal tar pitch was the primary determinant of dermal exposure, particularly for exposure to BAP. However, the task-based differences that were observed while controlling for pitch suggest that exposure to asphalt also contributes to dermal exposures. We found that dermal exposure was a significant determinant of total absorbed dose, suggesting that control strategies aimed at reducing occupational exposure to PACs should include an effort to minimize dermal exposure.

Inhalation and dermal exposure among asphalt paving workers.

The primary objective of this study was to identify determinants of inhalation and dermal exposure to polycyclic aromatic compounds (PACs) among asphalt paving workers. The study population included three groups of highway construction workers: 20 asphalt paving workers, as well as 12 millers and 6 roadside construction workers who did not work with hot-mix asphalt. During multiple consecutive work shifts, personal air samples were collected from each worker's breathing zone using a Teflon filter and cassette holder connected in series with an XAD-2 sorbent tube, while dermal patch samples were collected from the underside of each worker's wrist. All exposure samples were analyzed for PACs, pyrene and benzo[a]pyrene. Inhalation and dermal PAC exposures were highest among asphalt paving workers. Among paving workers, inhalation and dermal PAC exposures varied significantly by task, crew, recycled asphalt product (RAP) and work rate (inhalation only). Asphalt mix containing high RAP was associated with a 5-fold increase in inhalation PAC exposures and a 2-fold increase in dermal PAC exposure, compared with low RAP mix. The inhalation PAC exposures were consistent with the workers' proximity to the primary source of asphalt fume (paver operators > screedmen > rakers > roller operators), such that the adjusted mean exposures among paver operators (5.0 microg/m3, low RAP; 24 microg/m3, high RAP) were 12 times higher than among roller operators (0.4 microg/m3, low RAP; 2.0 microg/m3, high RAP). The dermal PAC exposures were consistent with the degree to which the workers have actual contact with asphalt-contaminated surfaces (rakers > screedmen > paver operators > roller operators), such that the adjusted mean exposures among rakers (175 ng/cm2, low RAP; 417 ng/cm2, high RAP) were approximately 6 times higher than among roller operators (27 ng/cm2, low RAP; 65 ng/cm2, high RAP). Paving task, RAP content and crew were also found to be significant determinants of inhalation and dermal exposure to pyrene. The effect of RAP content, as well as the fact that exposures were higher among paving workers than among millers and roadside construction workers, suggests that the PAC and pyrene exposures experienced by these paving workers were asphalt-related.

Urinary 1-hydroxypyrene and polycyclic aromatic hydrocarbon exposure among asphalt paving workers.

OBJECTIVES: Using urinary 1-hydroxypyrene (1-OHP) as a measure of total absorbed dose, the primary objective of this study was to evaluate the total effect of inhalation and dermal PAH exposures while considering other factors such as age, body mass index and smoking that may also have a significant effect on urinary 1-OHP. METHODS: The study population included two groups of highway construction workers: 20 paving workers and 6 milling workers. During multiple consecutive workshifts, personal air and dermal samples were collected from each worker and analyzed for pyrene. During the same work week, urine samples were collected pre-shift, post-shift and at bedtime each day and analyzed for 1-OHP. Distributed lag models were used to evaluate the independent effect of inhalation and dermal exposures that occurred at each of several preceding exposure periods and were used to identify the relevant period of influence for each pathway. RESULTS: The paving workers had inhalation (mean 0.3 micro g/m(3)) and dermal (5.7 ng/cm(2)) exposures to pyrene that were significantly higher than the milling workers. At pre-shift on Monday morning, following a weekend away from work, the pavers and millers had the same mean baseline urinary 1-OHP level of 0.4 micro g/g creatinine. The mean urinary 1-OHP levels among pavers increased significantly from pre-shift to post-shift during each work day, while the mean urinary 1-OHP levels among millers varied little and remained near the baseline level throughout the study period. Among pavers there was a clear increase in the pre-shift data during the work week, such that the average pre-shift level on day 4 (1.4 micro g/g creatinine) was 3.5 times higher than the average pre-shift results on day 1 (0.4 micro g/g creatinine). The results of the distributed lag model indicated that the impact of dermal exposure was approximately eight times the impact of inhalation exposure. Furthermore, dermal exposure that occurred during the preceding 32 h had a statistically significant effect on urinary 1-OHP, while the effect of inhalation exposure was not significant. CONCLUSIONS: We found that distributed lag models are a valuable tool for analyzing longitudinal biomarker data and our results indicate that dermal contact is the primary route of exposure to PAHs among asphalt paving workers. An exposure assessment of PAHs that does not consider dermal exposure may considerably underestimate cumulative exposure and control strategies aimed at reducing occupational exposure to asphalt-related PAHs should include an effort to reduce dermal exposure.

DNA strand breaks, oxidative damage, and 1-OH pyrene in roofers with coal-tar pitch dust and/or asphalt fume exposure.

OBJECTIVE: To determine the potential for asphalt fume exposure to increase DNA damage, we conducted a cross-sectional study of roofers involved in the application of roofing asphalt. METHODS: DNA strand breaks and the ratio of 8-hydroxydeoxyguanosine (8-OHdG) to 2-deoxyguanosine (dG) were measured in peripheral blood leukocytes of roofers. In addition, urinary excretion of 8-OHdG and 8-epi-prostaglandin F2alpha (8-epi-PGF) was also measured. The study population consisted of 26 roofers exposed to roofing asphalt and 15 construction workers not exposed to asphalt during the past 5 years. A subset of asphalt roofers (n = 19) was exposed to coal-tar pitch dust (coal tar) during removal of existing roofs prior to applying hot asphalt. Personal air monitoring was performed for one work-week to measure exposure to total particulates, benzene-soluble fraction of total particulates, and polycyclic aromatic compounds (PACs). Urinary 1-OH-pyrene levels were measured as an internal biomarker of PAC exposure. RESULTS: Full-shift breathing zone measurements for total particulates, benzene-solubles and PACs were significantly higher for coal-tar exposed workers than for roofers not exposed to coal tar. Similarly, urinary 1-OH-pyrene levels were higher in coal-tar exposed roofers than roofers not exposed to coal tar. Total particulates or benzene-soluble fractions were not associated with urinary 1-OH-pyrene, but PAC exposure was highly correlated with urinary 1-OH-pyrene. When stratified by 1-OH-pyrene excretion, DNA strand breaks increased in a dose-dependent manner, and leukocyte 8-OHdG/dG decreased in a dose-dependent manner. Significant changes in DNA damage appeared to be linked to PACs from coal-tar exposure, although asphalt fume alone was associated with a small but significant increase in urinary 1-OH-pyrene and DNA strand breaks. CONCLUSIONS: Results are consistent with previous reports that asphalt or coal-tar exposure can cause DNA damage. Urinary 8-epi-PGF remained relatively constant during the week for virtually all subjects, regardless of exposure indicating that neither asphalt nor coal-tar exposure induces an overt oxidative stress. A small, but statistically significant increase in 8OHdG was evident in end-of-week urine samples compared with start-of-week urine samples in roofers exposed to coal-tar. The increase in urinary 8OHdG coupled with the decrease in leukocyte 8-OHdG/dG, suggests that coal-tar exposure induces protective or repair mechanisms that result in reduced levels of steady-state oxidative-DNA damage.

Microvascular replantation of a traumatically amputated ear.

We describe the replantation of a traumatically severed auricle using microvascular anastomosis to reestablish blood flow to the ear. Microvascular reattachment of the severed auricle occurred 10 hours after the trauma. Postoperatively, adjunctive measures, including anticoagulation and the use of medicinal leeches, were used to relieve venous congestion of the replanted auricle. The replanted auricle healed completely with 100% survival, resulting in an essentially normal-appearing external ear. In the management of a traumatically severed auricle, microvascular replantation should be considered as the intervention of first choice in selected cases. If the procedure is successful, the cosmetic results are excellent; if it is not successful, a number of other reconstructive techniques remain as options.

Paraoccupational exposures to lead and tin carried by electric-cable splicers.

To test the hypothesis that electric-cable splicers contaminate their homes with lead and tin, nine splicers were matched with nine of their neighbors. House dust samples were collected in two areas within each home: a laundry room/dirty clothes area, and a composite sample from other areas in the house. Samples were analyzed by energy dispersive X-ray fluorescence for lead and tin (tin is a tracer to the occupational source of lead). The difference in the geometric mean lead concentrations in the laundry areas between the splicers' and neighbors' homes (1021 ppm and 390 ppm) was statistically significant (p < 0.025). The difference in concentrations from the other areas of the house (585 ppm and 329 ppm) was also significant (p < 0.05). Tin concentrations in house dust were very different between the two groups (p < 0.0005), suggesting that electric-cable splicers were contaminating their homes with lead and tin from work. Recommendations are included to prevent paraoccupational lead exposures by eliminating the pathways into the home. Another recommendation suggests that blood-lead levels be screened in children under the age of seven who live with electric-cable splicers.

Specific familial transmission in substance abuse.

In contrast to studies on alcoholism, there is little documentation on familial transmission of drug abuse. This study was designed to determine whether specific familial transmission of substance abuse occurs: a greater incidence of drug abuse in probands with a family history of drug abuse than in those with a family history of alcoholism. Probands were 305 consecutively admitted patients to an inpatient chemical dependency treatment center, whose substance abuse/dependence diagnoses were based on DSM-III criteria and a structured interview. Family history data were obtained from each proband. Log linear analysis investigated the association between family and proband substance abuse. As abuse of nonalcoholic substances was significantly greater in probands with family histories of drug abuse, specific familial transmission is suggested.

Evidence for the presence of mutagenic compounds other than chromium in particles from mild steel welding.

A modified Salmonella/microsome liquid culture assay was used to investigate the mutagenicity of the particulate fraction from mild steel welding. Previous reports have implicated compounds of chromium VI as the mutagenic and toxic agents in welding fumes, since only the particles from welding on stainless steel, which contains 15-25% chromium, were mutagenic, whereas particles from welding on mild steel, which contain less than 0.1% chromium, were not mutagenic or toxic. In this investigation, mild steel particles were shown to contain direct-acting and promutagenic compounds that induced frameshift mutations. The mutagenic agents, which were insoluble in sodium phosphate buffer, did not include chromium VI or organic compounds. Further, the expression of mutation appears to require a cell-particle interaction for the release of the mutagenic species from the particles.

Comparison between aqueous-phase and gas-phase exposure protocols for determining the mutagenic potential of nitrogen dioxide and the gas fraction of welding fumes.

Nitrogen dioxide and the gas fraction of welding fumes, a complex gas mixture which contains high concentrations of nitrogen dioxide, were tested for mutagenicity in Salmonella typhimurium tester strains, TA1535 and TA1538. A comparison between 2 exposure protocols, aqueous phase and gas phase, was made to evaluate the sensitivity of each in measuring the mutagenic potential of the gases. In the aqueous-phase exposure, a suspension of cells in an isotonic salt solution was exposed by bubbling the gas through the culture. In the gas-phase exposure, the plated cells were exposed to the gas in a chamber. For both gases tested, the gas-phase exposure resulted in a higher reversion frequency than the aqueous-phase exposure. Furthermore, we found that nitrogen dioxide accounted for only a fraction of the mutagenicity observed for the gas fraction of welding fumes.

Benzodiazepine interactions with central thyroid-releasing hormone binding sites: characterization and physiological significance.

Thyrotropin-releasing hormone (TRH) and several TRH analogs were examined in the [3H]-3-Me-His2-TRH ([3H]MeTRH) receptor-binding assay in rat amygdala, striatal and cortical membranes. The benzodiazepine, chlordiazepoxide, as reported in the literature was found to displace [3H]MeTRH with an IC50 value of 3.6 X 10(-7) M in amygdala membranes. Midazolam was, however, identified as being 6-fold more active than chlordiazepoxide with an IC50 value of 6.3 X 10(-8) M. The effect of these benzodiazepines on [3H]MeTRH binding did not appear to be related to their anxiolytic activity because the novel pyrazoloquinoline nonsedating anxiolytic, CGS 9896 was without effect on [3H]MeTRH binding at concentrations up to 1 X 10(-5) M. Chlordiazepoxide had similar activity in cortical membranes whereas midazolam was some 5 times less active in this preparation than in amygdala. Both compounds were weak displacers of [3H]MeTRH binding in striatal membranes, being at least two orders of magnitude less potent than in amygdala. In contrast TRH and its analogs, RX 77368 and DN-1417, were approximately 2 to 8 times more active in striatum than amygdala membranes. TRH and DN-1417 were less active in cortical membranes whereas RX 77368 was some three times more active than in striatum and amygdala. In three test procedures indicative of TRH agonist activity; thyroid-stimulating hormone release, reversal of pentobarbital sleeping time in mice and elevation of cerebellar cyclic GMP levels, the benzodiazepines were found to be devoid of activity, whereas TRH and related compounds produced their expected responses.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of a new thromboxane synthetase inhibitor, CGS-13080, in man.

CGS-13080 is a new potent selective inhibitor of thromboxane synthetase. This study reports the results of a safety and efficacy study of single oral doses in normal healthy volunteers. The compound was well tolerated by all subjects without evidence of any adverse reactions. Serum thromboxane B2 levels (the stable metabolic product of thromboxane A2) were significantly reduced after administration of the compound, with the maximal effect of a 99 per cent reduction occurring at 0.5 and 1 hour after administration. There was a concomitant increase in PGE2 and 6-keto-PGF1 alpha (the stable metabolic product of PGI2), suggesting a shunting of cyclic endoperoxide metabolism. The apparent half-life of the compound is about 1 hour, but return to 50 per cent of the original thromboxane B2 levels was achieved between 4 and 6 hours. Platelet aggregation to collagen and bleeding times failed to demonstrate significant changes after drug administration. Bleeding times showed a slight increase 2 hours after administration of the compound.

Aging-related decreases in hepatic mitochondrial and cytosolic delta-aminolevulinic acid synthase during experimental porphyria.

The basal- and allylisopropylacetamide-induced activities of the first enzyme of heme biosynthesis, delta-aminolevulinic acid synthase (ALAS) were measured in hepatic mitochondria and cytosol of young, adult, and aged Fisher 344 rats. The total cellular ALAS activity induced by allylisopropylacetamide decreased 67% with age. The specific activity of mitochondrial ALAS in normal and induced animals decreased with aging when assayed in whole or broken mitochondria. The levels of ALAS which accumulated in the cytosol after allylisopropylacetamide administration were proportionally greater in both the young and senescent than in the mature animals. During aging, no evidence for a fragile population of mitochondria in either normal or induced animals was observed suggesting that mitochondrial matrix proteins are not released during homogenization. The hepatic mitochondrial content decreased during aging when calculated using both a membrane-bound marker enzyme cytochrome oxidase and a matrix marker enzyme citrate synthase and was unaffected by allylisopropylacetamide treatment. This reduced mitochondrial content further diminishes the level of functional ALAS available in the liver during senescence. This study confirms the age-dependent decrease in mitochondria ALAS in normal and induced animals and also suggests an age-related change in the process by which cytosolic ALAS is translocated into the mitochondria.

CGS 8216: receptor binding characteristics of a potent benzodiazepine antagonist.

CGS 8216 is a novel nonbenzodiazepine that inhibited 3H-flunitrazepam (3H-FLU) binding to rat synaptosomal membranes in vitro at subnanomolar concentrations. It prevented the in vivo labeling of brain benzodiazepine receptors by 3H-FLU with the same potency as diazepam when given orally to mice. Pharmacologic tests showed that it was devoid of benzodiazepine-like activity but it antagonized the actions of diazepam in these tests. It did not interact with alpha- or beta- adrenergic, H1-histaminergic or GABA receptors but it inhibited adenosine-activation of cyclic AMP formation. Studies with 3H-CGS 8216 demonstrated that it bound specifically and with high affinity to rat forebrain membranes and was displaced by drugs with an order of potencies similar to that observed when 3H-diazepam and 3H-FLU were used as radioligands. The regional distribution of 3H-CGS 8216 binding sites in the brain was also similar to that of 3H-FLU. Dissociation of 3H-CGS 8216 binding was slow at 0 degrees C but increased with temperature and was almost complete within 1 min at 37 degrees C. Scatchard analyses were linear, yielding KD values of 0.044, 0.11 and 0.18 nM at 0, 25 and 37 degrees C, respectively; the Bmax value did not change appreciably with temperature and was approximately 1000 fmoles/mg protein. Using 3H-FLU, the value for Bmax as well as for the KD increased with temperature. The total number of binding sites determined for 3H-FLU was greater than that for 3H-CGS 8216 at each temperature. CGS 8216 exhibited mixed-type inhibition of 3H-FLU binding. GABA did not stimulate 3H-CGS 8216 binding whereas it enhanced 3H-FLU binding. CGS 8216 may be a useful ligand for probing the antagonist properties of the benzodiazepine receptor and is likely to exhibit interesting therapeutic effects.