Factors influencing the difference between maternal and cord blood lead.

AIMS: To determine the factors that affect why some infants receive higher exposures relative to the mother's body burden than do others. METHODS: A total of 159 mother-infant pairs from a cohort of women receiving prenatal care at Magee-Womens Hospital in Pittsburgh, PA from 1992 to 1995 provided blood samples at delivery for lead determination. The difference between cord and maternal blood lead concentration (PbB) and a dichotomous variable indicator of higher cord than maternal PbB, were examined as indicators of relative transfer. Women were interviewed twice during the pregnancy about lifestyle, medical history, calcium nutrition, and physical activity. RESULTS: Higher blood pressure was associated with relatively greater cord compared with maternal PbB, as was maternal alcohol use. Sickle cell trait and higher haemoglobin were associated with a lower cord relative to maternal blood lead PbB. No association was seen with smoking, physical exertion, or calcium consumption. CONCLUSION: While reduction in maternal exposure will reduce fetal exposure, it may also be possible to mitigate infant lead exposure by reducing transfer from the pregnant woman. Interventions aimed at reducing blood pressure and alcohol consumption during pregnancy may be useful in this regard.

Synthesis, dark toxicity and induction of in vitro DNA photodamage by a tetra(4-nido-carboranylphenyl)porphyrin.

The total synthesis of tetra(4-carboranylphenyl)porphyrins 4 and 6 and their zinc(II) complexes 5 and 7 are described. These compounds were characterized by analytical and spectroscopic methods and, in the case of 5, by X-ray crystallography. The water-soluble nido-carboranylporphyrins 6 and 7 were found to have low dark toxicity towards V79 hamster lung fibroblast cells, using a clonogenic assay (50% colony survival, CS(50)>300 microM). Upon light activation nido-carboranylporphyrin 6 effectively induced DNA damage in vitro. Two different methods were used to assess the extent of DNA damage: the super-coiled to nicked DNA and the alkaline Comet assay using human leukemia K562 cells. Significant PDT-induced DNA damage was observed for porphyrin 6 using both assays, compared to light-only and porphyrin-only experiments. It is concluded that this type of nido-carboranylporphyrin is a promising sensitizer for both the boron neutron capture therapy and the photodynamic therapy of tumors.

Patterns and determinants of blood lead during pregnancy.

The pattern of blood lead during pregnancy was investigated in a cohort of 195 women who, between October 1992 and February 1995, entered prenatal care at Magee-Womens Hospital in Pittsburgh, Pennsylvania, by week 13 of pregnancy. Blood was drawn as many as five times, once in each of the first two trimesters and a maximum of three times in the third trimester. Blood lead determinations were made by atomic absorption spectrophotometry. Potential sources or modifiers of lead exposure were collected by interviews, including sociodemographic, pregnancy history, occupational, and lifestyle data. Results confirmed a previously reported U-shaped curve in blood lead concentration during pregnancy as well as findings that blood lead levels increase with age, smoking, lower educational level, and African-American race and decrease with history of breastfeeding and higher intake of calcium. Additionally, interactions were found between time since last menstrual period and both maternal age and calcium. Specifically, older mothers showed steeper increases in blood lead concentrations during the latter half of pregnancy than did younger mothers, and intake of calcium had a protective effect only in the latter half of pregnancy, an effect that became stronger as pregnancy progressed. These findings provide further evidence that lead is mobilized from bone during the latter half of pregnancy and that calcium intake may prevent bone demineralization.

Risk analysis for thoracoscopic lung volume reduction: a multi-institutional experience.

OBJECTIVE: Most reports of thoracoscopic lung volume reduction (TLVR) are relatively small and early experiences from a single institution, factors which limit both the statistical validity and the applicability to the population at large. In order to address these shortcomings we undertook an analysis of the TLVR experience at five separate institutions to assess operative morbidity and identify predictors of mortality. METHODS: Questionnaires were sent to four groups of surgical investigators at five institutions actively performing TLVR. Data was requested regarding preoperative, operative and postoperative parameters. Twenty-five potential predictors of mortality were analyzed and seven proved to be at least marginally significant (P<0.10). These parameters were entered into a stepwise logistic regression analysis to identify independent predictors. RESULTS: The 682 patients (415 males, 267 females, mean age 64.0 years) underwent unilateral (410) or bilateral (272) TLVRs. Overall, operative mortality was 6% with half of the deaths resulting from respiratory causes. The remaining patients were discharged to home (88%), a rehabilitation facility (4%) or a ventilator facility (2%). There were 25 perioperative factors chosen representing clinically important indices such as spirometry, oxygenation, functional status, clinical and demographic variables. Univariate analysis identified seven variables as predictors of mortality (P<0.10) and these were entered into a stepwise logistic regression analysis. Only age, 6-min walk, gender (male 8%, female 3% mortality) and the procedure performed (unilateral 4.6%, bilateral 8%) were independent predictors while preoperative steroid therapy, preoperative oxygen administration, and time since smoking cessation dropped out of the model. The specific institution, learning curve (early vs. late experience), type of lung disease, spirometric indices and predicted maximum VO(2) were not significant predictors. CONCLUSION: This experience suggests that unilateral and bilateral lung volume reduction procedure can be performed with acceptable morbidity and mortality. Although age, gender, exercise capacity and the procedure performed are all independent predictors of mortality, the risk of operative death did not appear excessive in this fragile patient subset.

Long-term survival after thoracoscopic lung volume reduction: a multiinstitutional review.

BACKGROUND: It has been suggested that bilateral thoracoscopic lung volume reduction (BTLVR) yields significantly better long-term survival than unilateral thoracoscopic lung volume reduction (UTLVR). METHODS: All perioperative data were collected at the time of the procedure. Follow-up data were obtained during office visits or by telephone. RESULTS: A total of 673 patients underwent thoracoscopic LVR: 343 had either simultaneous or staged BTLVR and 330, UTLVR. As of July 1998, follow-up was available on 667 (99%) of the 673 patients with a mean follow-up of 24.3 months. The patients in the BTLVR group were significantly younger (62.6+/-8.0 years versus 65.4+/-8.1 years; p < 0.0001), had a higher preoperative arterial oxygen tension (69.7+/-12 mm Hg versus 65.3+/-11 mm Hg; p < 0.0001), and had a superior preoperative 6-minute walk performance (279.9+/-93.6 m [933+/-312 feet] versus 244.5+/-101.4 m [815+/-338 feet] p < 0.0001). There was no difference in the operative mortality rate between the two groups (UTLVR, 5.1%, and BTLVR, 7%). Actuarial survival rates for the UTLVR group at 1 year, 2 years, and 3 years were 86%, 75%, and 69%, respectively versus 90%, 81%, and 74%, respectively, for the BTLVR group (p = not significant). CONCLUSIONS: Contrary to previous reports, survival after BTLVR was not superior to that after UTLVR even though the former group appeared to have a lower risk preoperatively because of younger age, higher arterial oxygen tension, more advantageous anatomy, and better functional status. Despite thoracoscopic LVR, the actuarial mortality rate approached 30% at 3 years, and this calls into question whether this procedure offers any survival advantage to patients with end-stage emphysema.

Thoracoscopic lung volume reduction surgery reduces dyspnea and improves exercise capacity in patients with emphysema.

Improved ventilation and exercise capacity follows thoracoscopic lung volume reduction surgery (TLVRS) in patients with severe emphysema. This improvement could be related to changes in inspiratory and expiratory flows following surgery, with consequent improvement in dyspnea indices. Changes in inspiratory/expiratory flows at rest and exercise and their relation to subjective improvement in dyspnea after TLVRS are not well known. We studied 25 patients with severe emphysema who underwent unilateral TLVRS performed in well-defined zones with decreased perfusion in nuclear medicine lung scans. Early follow-up after surgery (4.2 +/- 0.8 mo) showed significant improvements in exercise tolerance: The distance covered over a 6 min walk test increased from 934 +/- 297 to 1,071 +/- 241 ft (p = 0.01). Exercise tolerance using a bicycle ergometer showed increased exercise endurance from 4.43 +/- 1.7 to 5.71 +/- 1.8 min (p < 0.001). The maximum workload tolerated increased from 37 +/- 19 to 52 +/- 21 W (p < 0.01) and VO2 max changed from 9.7 +/- 2 to 11.8 +/- 3 (ml.kg)/min (p < 0.01). This increment was achieved by generating significantly larger minute ventilation (VE), from 24 +/- 11 to 29 +/- 10 L/min, reached through larger tidal volumes (increasing from 951 +/- 330 to 1,145 +/- 367 ml), while maintaining the same maximum respiratory rates. Increased VE was also accompanied by significant increases in both average inspiratory and expiratory flows measured during exercise: from 0.89 +/- 0.41 L/s to 1.06 +/- 0.08 L/s, and from 0.77 +/- 0.37 to 0.90 +/- 0.32 L/s respectively (p < 0.01). The parallel increment in flows resulted in constant T1/Ttot relationship. These functional changes correlated with increased inspiratory flows at rest measured with pulmonary function tests (forced inspiratory volume in one s [FIV1], expiratory flows [FVC, FEV1], and increased maximum voluntary ventilation [MVV]) following the surgically induced reduction in residual volume (RV). These objective changes occurred parallel to improved dyspnea indices. The Baseline Focal Score was 3.36 +/- 1.47 and the Transition Focal Score was 6.12 +/- 0.7. The objectively measured variables at rest that best correlated with subjective improvement in dyspnea were the change in MVV, change in resting arterial PaO2, and change in FEV1 following TLVRS. Exercise variables did not have significant correlation with subjective markers indicating improvement in dyspnea, with the exception of the change in Dyspneic Index [(VE/MVV)100] at maximum exercise.

Histopathologic diagnosis made in lung tissue resected from patients with severe emphysema undergoing lung volume reduction surgery.

STUDY OBJECTIVES: This study reports histopathologic findings in a group of emphysema patients who underwent thoracoscopic lung volume reduction surgery (75) or sternotomy (five) with the purpose to induce functional improvement and relief of dyspnea. Immediate outcome and complications were correlated to histologic patterns. DESIGN: Histopathologic material obtained in lung volume reduction surgery in 80 consecutive patients was analyzed. Thirty patients who had other histopathologic diagnoses in addition to emphysema were grouped and compared with 50 patients found to have emphysema exclusively. Postoperative outcome and preoperative lung function variables were compared. MEASUREMENTS AND RESULTS: All patients had severe obstructive lung disease and significant air trapping preoperatively documented by pulmonary function testing. All had severe exertional dyspnea. All had chest radiographs, CT, and nuclear medicine lung scans consistent only with emphysema. All portions of resected lung tissue were weighed, lung volume was estimated, and routine histopathologic studies were made. Thirty patients (37.5%) had unsuspected findings such as interstitial fibrosis, noncaseating granulomatosis, chronic inflammation, and unsuspected neoplasia (three carcinomas, one carcinoid). Retrospective review of imaging studies in these patients failed to show infiltrative processes. The average lung weight resected in this group was significantly heavier (65+/-18 g) compared with the other group (56+/-13 g), although both had the same estimated lung volume. Average number of days requiring chest tubes and length of hospitalization was also significantly higher (12.8+/-19 vs 6.4+/-5 days with chest tubes and 17.4+/-22 vs 8.5+/-6 days of hospitalization, respectively). None of the preoperative pulmonary function tests variables were different between the two groups. Serious postoperative complications were more frequent in these patients compared with those who showed only emphysema. CONCLUSIONS: A significant portion of patients diagnosed as having severe emphysema will have other unsuspected histologic findings. When subjected to lung volume reduction surgery, this subgroup will have more serious complications and longer periods of air leaks, requiring longer hospitalization time. Retrospective review of imaging studies and preoperative pulmonary function tests used to select patients for lung volume reduction failed to identify this subgroup.

Hemodynamics and gas exchange after single lung transplantation and unilateral thoracoscopic lung reduction.

BACKGROUND: Single lung transplantation and recently thoracoscopic lung reduction (TLR) have become surgical alternatives to manage emphysema. We report here early outcomes of 10 single lung transplant (SLT) recipients with severe emphysema compared with 10 patients treated with unilateral TLR. METHODS: Ten consecutive recipients of (SLT) and 10 patients undergoing unilateral TLR were studied. Both groups had measurements of preoperative pulmonary function and arterial blood gases. Hemodynamic measurements were made by use of a right ventricular ejection fraction/volumetric pulmonary artery catheter during and immediately after surgery in both groups to compare hemodynamic and gas exchange response in each procedure. Pulmonary function tests were repeated 3 months and 1 year after surgery. Complications and functional outcome are reported. RESULTS: Both groups had the same severity of obstructive disease (mean forced expiratory volume in 1 second = 20% +/- 5% for the SLT group and 23% +/- 9% for the TLR group) and similar patterns of right ventricular dysfunction. During operation, SLT recipients showed worse hypercapnia and pulmonary hypertension than TLR subjects when ventilation and perfusion to the operative lung were interrupted. Patients undergoing TLR only had interrupted ventilation, which was transiently reversed when severe hypoventilation or hypoxemia occurred. All patients undergoing TLR were extubated immediately after surgery. SLT recipients were extubated an average of 42 hours later. Pulmonary function testing performed 3 months after surgery showed improvement in both groups. SLT recipients showed larger improvements in airflow but comparable improvements in forced vital capacity. Both groups achieved similar improvements in gas exchange. This trend continued a year after surgery. Patients undergoing TLR were not subjected to complications of immunosuppressive therapy or exposed to opportunistic infections. CONCLUSIONS: Early results show TLR as an acceptable alternative to SLT in carefully selected patients with the same severity of obstructive lung disease. Long-term follow-up studies are needed to establish long-term differences in functional outcome and development of complications. TLR may be an option for patients with severe dyspnea related to emphysema who do not meet criteria for transplantation.

Nursing care of the thoracoscopic lung volume reduction patient.

BACKGROUND: Several methods to surgically enhance pulmonary function and improve the quality of life in patients with bullous emphysema are currently being evaluated. One of these methods, lung volume reduction, is performed in patients with bullous emphysema that can no longer be well managed with medical therapy. OBJECTIVES: The focus of this article is to review bullectomy via unilateral thoracoscopy with an endoscopic stapler in the management of end-stage pulmonary emphysema, and to discuss nursing care of these patients. METHODS: An experimental study was used, including review of the literature and analysis of clinical experience using chi-square and t test analyses of pre- and postoperative variables. RESULTS: At 3-month follow-up there were significant improvements in forced expiratory volume in 1 second, forced vital capacity, minute volume ventilation, partial pressure of oxygen, residual volume, and 6-minute walk when pre- and postoperative parameters were compared. Operative mortality was 4%, with the most common complication being prolonged air leak, occurring in 30% of patients studied. CONCLUSIONS: There is now consistent preliminary information to support the concept that lung volume reduction improves pulmonary function and quality of life in a significant percentage of patients.

Unilateral video-assisted thoracic surgical lung reduction.

BACKGROUND: Lung reduction has been demonstrated to be a promising treatment for end-stage emphysema when performed on both lungs via sternotomy. The role for a thoracoscopic approach has not yet been determined. METHODS: Unilateral video-assisted thoracic surgical lung reduction was performed on 50 patients for the treatment of end-stage emphysema. There were 34 men and 16 women with a mean age of 61.5 years (range, 31 to 78 years). Emphysema was secondary to smoking in 45 patients (90%), and alpha 1-antitrypsin deficiency in 5 patients (10%), 4 of whom had smoked in the past. Lung reduction was performed unilaterally using a thoracoscope and a stapled resection without the routine use of bovine pericardium. The side to be operated on and site of resection were determined preoperatively by examination of the perfusion and computed tomographic scans of the lungs. The average amount of lung removed was 59 +/- 15 g (range, 29 to 111 g). RESULTS: Morbidity included prolonged air leak in 15 patients (30%), bleeding in 3 (6%), pneumonia requiring reintubation in 3 (6%), myocardial infarction in 1 (2%), and perforated ulcer in 1 (2%). Seven patients (14%) required a second thoracic procedure for management of these complications. Two patients died, for an operative mortality of 4%. Follow-up obtained between 1 and 3 months in 25 patients revealed significant improvement in forced expiratory volume in 1 second (0.71 to 0.95 L; p < 0.001), forced vital capacity (2.24 to 2.58 L; p < 0.01), and oxygen tension (59 to 67 mm Hg; p < 0.01). The improvement in functional capacity as measured by 6-minute walk approached statistical significance (771 to 923 ft; p = 0.06). CONCLUSIONS: Significant subjective improvement in dyspnea has been noted in 41 of 48 hospital survivors (85%). For patients with end-stage emphysema, unilateral video-assisted thoracic surgical lung reduction appears to be a preferable alternative to standard medical management.

Formate in serum and urine after controlled methanol exposure at the threshold limit value.

Methanol will be present as a new air pollutant when methanol-powered vehicles are introduced in the United States. Little is known about the effect of low-dose methanol exposure. It is controversial whether or not formate, the main metabolite responsible for methanol's acute toxicity, is a sensitive biological marker of toxicity or exposure. We studied the effect of a 4-hr exposure at rest to 200 ppm of methanol vapors on endogenous serum formate and on urinary formic acid excretion. A randomized, double-blind study of human exposure to a constant concentration of methanol was performed in a whole-body exposure chamber. Twenty-six healthy volunteers, each serving as his or her own control, participated in sham and methanol exposures. Urine (at 0, 4, 8 hr) and serum specimens (15 time points over 8 hr) collected before, during, and after the exposure were measured for formate. We found no significant differences in serum formate concentration between exposure and control conditions either at any time point or for area under the curve. Mean concentrations at the end of the exposure were: exposed 14.28 +/- 8.90 mg/l and control 12.68 +/- 6.43 mg/l. A slight, but nonsignificant (p = 0.08), increase in urine formate excretion rate was found at 4 hr (exposed 2.17 +/- 1.69 mg/4 hr and control 1.67 +/- 1.02 mg/4 hr). Age, sex, folic acid level, and smoking were not significant covariates. At 200 ppm, methanol exposure does not contribute substantially to endogenous formate quantities. Serum and urine formate determinations are not sensitive biological markers of methanol exposure at the threshold limit value.

Factors influencing bone lead concentration in a suburban community assessed by noninvasive K x-ray fluorescence.

OBJECTIVE: To determine the influence of demographic, exposure and medical factors on the bone lead concentration of subjects with background (nonindustrial) environmental lead exposure. DESIGN: Survey. SETTING: Suburban residential community. PARTICIPANTS: A total of 101 subjects (49 males, 52 females; aged 11 to 78 years) were recruited from 49 of 123 households geographically located in a suburban residential neighborhood unexposed to any major source of industrial lead emissions. MAIN OUTCOME MEASUREMENTS: Cortical bone lead concentrations in the midshaft of the tibia were noninvasively measured by in vivo K x-ray fluorescence. Blood lead concentrations were measured by anodic stripping voltammetry. An administered questionnaire assessed potential sources of lead exposure and medical conditions affecting bone metabolism. RESULTS: After the exclusion of one outlier, log-transformed bone lead concentration was highly correlated with age (r = .71; P < or = .0001). Bone lead concentration showed no significant change up to age 20 years, increased with the same slope in men and women between ages 20 and 55 years, and then increased at a faster rate in men older than 55 years. In addition to the variables age and sex, the best fitting multiple regression model for bone lead concentration (R2 = .66; P < or = .0001) revealed a positive correlation with total pack-years of cigarette smoking and a negative correlation with a history of having nursed an infant for longer than 2 weeks. Blood lead concentrations of the subjects were low (geometric mean, 0.24 mumol/L [4.9 micrograms/dL]) and after log transformation were weakly correlated with log-transformed bone lead concentration (r = .23; P = .02). CONCLUSIONS: The age- and sex-related increases in bone lead concentration found by K x-ray fluorescence concur with published postmortem studies of bone lead concentration and are consistent with the kinetics of bone turnover and secular trends in lead exposure. These data help to establish a reference range for assessing the lead burden of other populations with environmental or occupational lead exposure.

Urinary protein markers in pesticide applicators during a chlorinated hydrocarbon exposure.

A previous study of 16 pesticide applicators showed that N-acetylglucosaminidase (NAG) excretion during exposure to the soil nematocide, 1,3-dichloropropene (DCP), was correlated with DCP dose and the excretion of its major metabolite, N-acetyl-S-(cis-3-chloroprop-2-enyl)-cysteine (3CNAC). Using the same urine samples, two other proteins were measured: low concentrations of albumin ("microalbuminuria," ALB) and retinol-binding protein (RBP). For each worker there were five consecutive urine collection intervals (6-8 hr each): overnight prior to exposure, morning work shift, afternoon work shift, evening after work, and overnight. Paired comparisons of each interval to baseline (first interval) for each protein excretion (creatinine corrected) did not reveal significant increases. However, amounts of renal proteins per interval, in contrast to creatinine-corrected concentrations, were more strongly correlated with each other and with 3CNAC concentrations within samples. Clear dichotomous differences in urinary protein excretion were seen for high versus low exposure (< or > 1.5 mg 3CNAC excretion/day) for NAG and RBP, but not for ALB. Based on earlier findings of a slight elevation of NAG and the minimal changes reported herein for RBP, the possible effects of short-term workplace exposure to DCP on renal protein excretion appear to be mild.

Effects of hyperparathyroidism on blood lead concentrations in man.

To investigate whether hyperparathyroidism has an effect on blood lead (Pb) concentrations and whether parathyroidectomy will alter blood Pb concentrations, we studied 15 subjects with primary hyperparathyroidism (HPTH) and 7 control subjects with thyroid nodules (TC). Blood Pb concentrations were determined several weeks prior to surgery and then again 4 months later. A reference group (REF) of nonsurgical lab/office workers was examined over the same periods of time. Initial mean blood Pb concentrations were 6.6 +/- 2.8, 6.0 +/- 2.9, and 5.0 +/- 1.7 micrograms/dl for the HPTH, TC, and REF groups (not significantly different), respectively. The mean percentage changes in blood Pb (before vs after) were -13.9, -4.9, and -6.1%. While the paired changes in blood Pb concentrations within the HPTH group were significant (P < 0.05), the percentage changes compared to either of the TC or REF groups were not significantly different. The percentage change in blood Pb correlated with the percentage change in serum calcium across all subjects (r = 0.5176, P = 0.0024, n = 24), although this correlation was not significant within any group alone. The HPTH group demonstrated expected changes in serum calcium, parathyroid hormone, and alkaline phosphatase concentrations. Three of the HPTH subjects received a CaNa2 EDTA chelation challenge (1 g intramuscularly) before and 4 months after surgery. Chelated amounts of Pb (microgram/24 hr before vs after) were 52 vs 38, 42 vs 47, and 60 vs 34. These data indicate that in the high bone turnover state of hyperparathyroidism that Pb concentrations in the blood-soft tissue compartment, and probably Pb mass, are not likely to be different from other individuals. Also parathyroidectomy results in a lowering of blood Pb concentrations possibly due to parallel movements of calcium.

Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers.

The safety, efficacy and pharmacokinetic parameters of 5 g of hydroxocobalamin given intravenously, alone or in combination with 12.5 g of sodium thiosulfate, were evaluated in healthy adult men who were heavy smokers. Sodium thiosulfate caused nausea, vomiting, and localized burning, muscle cramping, or twitching at the infusion site. Hydroxocobalamin was associated with a transient reddish discoloration of the skin, mucous membranes, and urine, and when administered alone produced mean elevations of 13.6% in systolic and 25.9% in diastolic blood pressure, with a concomitant 16.3% decrease in heart rate. No other clinically significant adverse effects were noted. Hydroxocobalamin alone decreased whole blood cyanide levels by 59% and increased urinary cyanide excretion. Pharmacokinetic parameters of hydroxocobalamin were best defined in the group who received both antidotes: t1/2 (alpha), 0.52 h; t1/2 (beta), 2.83 h; Vd (beta), 0.24 L/kg; and mean peak serum concentration 753 mcg/mL (560 mumol/L) at 0-50 minutes after completion of infusion. Hydroxocobalamin is safe when administered in a 5 gram intravenous dose, and effectively decreases the low whole blood cyanide levels found in heavy smokers.

Flavin-containing monooxygenase-dependent stereoselective S-oxygenation and cytotoxicity of cysteine S-conjugates and mercapturates.

The metabolism of cysteine S-conjugates of both cis- and trans-1,3-dichloropropene in the presence of rat kidney microsomes and purified flavin-containing monooxygenase from hog liver was investigated in vitro. Preliminary studies with isolated rat kidney cells demonstrated that cysteine S-conjugates were quite toxic to the cells in a process which was consistent with a role of the flavin-containing monooxygenase in the bioactivation of the nephrotoxins. Putative S-oxide metabolites of cysteine S-conjugates were chemically synthesized, and diastereomers were separated and identified by spectroscopic means. The metabolic products of cysteine S-conjugates were identified by comparing the chemical properties of the metabolites with authentic synthetic cysteine S-conjugate S-oxides. Surprisingly, S-conjugate S-oxygenase activity was not observed with rat kidney microsomes but was present when cysteine S-conjugates were incubated with the highly purified flavin-containing monooxygenase from hog liver. The kinetic parameters indicated that considerable S-oxygenase stereoselectivity and structural selectivity was observed: cis cysteine S-conjugates were preferred substrates and N-acetylation of cysteine S-conjugates decreased substrate activity. S-Oxygenation was considerably diastereoselective and diastereoselectivity was much greater for cysteine S-conjugates with higher Vmax values. Cysteine S-conjugate S-oxides were not indefinitely stable, and under certain conditions, the S-oxides underwent a [2,3]-sigmatropic rearrangement to acrolein. Formation of acrolein or other electrophilic products from S-(chloropropenyl)cysteine conjugate S-oxides may contribute to the renal effects observed for S-(chloropropenyl)cysteine conjugates.(ABSTRACT TRUNCATED AT 250 WORDS)

Utility and reliability of emergency toxicologic testing.

Emergency physicians using toxicologic testing should learn the capabilities of their laboratories: What is detectable? What is not? What is the expected turnaround time? Do pharmacologic relationships exist? In ordering test requests, the laboratory should allow the physician to order limited test combinations, and the physician can assist the laboratory in the search for unknowns by indicating the running diagnosis and suspected drugs. Only a few drugs require quantitation in serum in order to assist in therapeutic decisions. Urine drug screening is useful in documenting intoxications due to drugs and frequently demonstrates more drugs or drugs other than those clinically expected. The impact of findings from emergency drug screening upon diagnosis and therapy appears to be low. Although comprehensive drug screening in the emergency setting has a better positive predictive value ("rule-in") than negative predictive value, toxicologic screening may be useful as a "rule-out" test in other diagnostic applications of lower prior probability. Future directions in laboratory diagnosis of the intoxicated patient are likely to include growth in new immunoassays with limited applications, but with rapid turnaround within the Emergency Department. Also, with improvements in technology, screening of serum drugs will become more common, including the discovery of more quantitative relationships between serum concentration and toxic effects.

Influence of race, tobacco use, and caffeine use on the relation between blood pressure and blood lead concentration.

A number of studies have suggested a small to moderate positive relation between blood pressure and blood lead concentration in males (2-4 mmHg/In(microgram/dl]. However, this 1986 study of San Francisco bus drivers suggests larger relations in black males (n = 132) for both systolic pressure (7.5 mmHg/In(microgram/dl] and diastolic pressure (4.7 mmHg/In(microgram/dl] at very low blood lead concentrations (2-21 micrograms/dl). This increase appears to result from negative confounding, particularly after taking into account tobacco use. Relations are even larger in blacks who infrequently use caffeine (16.7 and 10.4 mmHg/In(microgram/dl) for systolic and diastolic pressure, respectively). In contrast, a negative relation between systolic pressure and blood lead concentration (-5.7 mmHg/In(microgram/dl] is suggested in nonblack males (n = 117). These findings indicate that race, lead accumulation, and physiologic effects related to caffeine use (e.g., catecholamine effects) may interact to produce marked differences in effect on blood pressure.

Effects of 1,3-dichloropropene on the kidney of Fisher 344 rats after pretreatment with diethyl maleate, buthionine sulfoximine, and aminooxyacetic acid.

Acute nephrotoxicity of cis/trans-1,3-dichloropropene (DCP) was assessed in male Fisher 344 rats. Pretreatment of rats with corn oil, aminooxyacetic acid (AOA), buthionine sulfoximine (BSO), or diethyl maleate (DEM) was given intraperitoneally 1 h or 4 h prior to injection of DCP. Doses of DCP were 0, 25, 50, and 75 mg/kg intraperitoneally (4-5 animals per dose/pretreatment group). Urine was collected for 24 h. Excretion of creatinine, phosphorus, protein, N-acetylglucosaminidase (NAG), and the major metabolite of DCP, N-acetyl-S-(cis-3-chloroprop-2-enyl)-cysteine (3CNAC), was measured. Excretion of the metabolite, 3CNAC, increased in a dose-related manner from 0 to 50 mg/kg of DCP, but further increases were not seen at the 75 mg/kg dose. The pretreatments produced no alterations in the amounts of metabolite excreted when compared to corn oil controls. Zero-order metabolism or impaired metabolism is suggested to be occurring at high doses of DCP. The AOA pretreatment group showed no increase in the excretion of NAG, whereas other pretreatments (corn oil, BSO, DEM) showed elevations of NAG excretion at the highest DCP doses. AOA inhibits renal beta-lyase, an enzyme that mediates cleavage of mercapturic acid metabolites to toxic products. Since NAG excretion was not elevated in response to DCP with AOA pretreatment and was not raised by pretreatments that deplete glutathione, it is suggested that nephrotoxic effects of DCP may be mediated through the mercapturic acid metabolites on the kidney, rather than due to glutathione depletion per se.

Biological monitoring of dichloropropene: air concentrations, urinary metabolite, and renal enzyme excretion.

Fifteen applicators of dichloropropene (DCP) were studied for personal air exposure to DCP, excretion of the metabolite of DCP (3CNAC), and excretion of the renal tubular enzyme, N-acetyl glucosaminidase (NAG). Each was studied for four 6-8 h consecutive intervals following baseline determinations of 3CNAC and NAG excretion. In accord with pilot data, 24-h urinary excretion of 3CNAC (mg) correlated well with exposure product for DCP (min exposed.mg/m3), r = 0.854, p less than .001. A more precise correlation of the air exposure product with urinary excretion of 3CNAC was discerned by using the morning urine after the previous day of exposure (micrograms/mg of creatinine), r = 0.914, p less than .001. Four workers had clinically elevated activity of NAG (greater than 4 mU/mg creatinine) in any of their urine collections after baseline. Nine workers showed greater than 25% increases in NAG excretion when compared to baseline. Dichloropropene air exposure products of greater than 700 mg.min/m3 or excretion of greater than 1.5 mg 3CNAC/d distinguished abnormally high daily excretion of NAG. These data demonstrate a firm positive relationship between air exposure and internal exposure, and a possible subclinical nephrotoxic effect in DCP workers.