Inability of GSTT1 to activate iodinated halomethanes to mutagens in Salmonella.

Drinking water disinfection by-products (DBPs), including the ubiquitous trihalomethanes (THMs), are formed during the treatment of water with disinfectants (e.g., chlorine, chloramines) to produce and distribute potable water. Brominated THMs (Br-THMs) are activated to mutagens via glutathione S-transferase theta 1 (GSTT1); however, iodinated THMs (I-THMs) have never been evaluated for activation by GSTT1. Among the I-THMs, only triiodomethane (iodoform) has been tested previously for mutagenicity in Salmonella and was positive (in the absence of GSTT1) in three strains (TA98, TA100, and BA13), all of which have error-prone DNA repair (pKM101). We evaluated five I-THMs (chlorodiiodomethane, dichloroiodomethane, dibromoiodomethane, bromochloroiodomethane, and triiodomethane) for mutagenicity in Salmonella strain RSJ100, which expresses GSTT1, and its homologue TPT100, which does not; neither strain has pKM101. We also evaluated chlorodiiodo-, dichloroiodo-, and dibromoiodo-methanes in strain TA100 +/- rat liver S9 mix; TA100 has pKM101. None was mutagenic in any of the strains. The I-THMs were generally more cytotoxic than their brominated and chlorinated analogues but less cytotoxic than analogous trihalonitromethanes tested previously. All five I-THMs showed similar thresholds for cytotoxicity at ~2.5 µmoles/plate, possibly due to release of iodine, a well-known antimicrobial. Although none of these I-THMs was activated by GSTT1, iodoform appears to be the only I-THM that is mutagenic in Salmonella, only in strains deficient in nucleotide excision repair (uvrB) and having pKM101. Given that only iodoform is mutagenic among the I-THMs and is generally present at low concentrations in drinking water, the I-THMs likely play little role in the mutagenicity of drinking water.

[Freon gas frostbite: an unusual burn evolving in two stages]. / Gelure au gaz fréon : une brulure atypique évoluant en deux temps.

Freon gas is a halogenated derivative widely used in refrigeration and air conditioning. It is maintained at a temperature below -41°C and its contact with skin may cause very serious burns. This is usually an accident at work and the burns affect the hands of patients first. Unfortunately, early clinical presentation is often reassuring and does not reflect the actual depth of the injury. Few cases of this injury are reported and no treatment protocol is established at this time. We present two cases of frostbite by freon gas, initially evaluated at a stage of superficial burns and evolved spontaneously in a few days to full thickness burns necessitating surgical treatment by excision and skin grafting. This evolution in two phases has never been described and could help to better understand the pathophysiology of this frostbite and the possibilities of management.

A comparative study of patients' preferences and sensory perceptions of three forms of inhalers among Thai asthma and COPD patients.

In 9 study centers, 419 patients with asthma or COPD were randomized to receive two forms of salbutamol metered-dose-inhalers (MDIs), i.e. CFC-driven MDI, non-CFC (HFA) MDI and one salbutamol dry powder inhaler (DPI), in a multi-center, comparative, cross-over and randomized study, performed to facilitate the formulation of a strategic plan to phase out CFC MDIs. After having received all three forms of test products, the patients completed an evaluation questionnaire indicating their preferences, likelihood of treatment compliance on each product and the easiest one to use. Statistical analysis showed that the CFC MDI was significantly less irritating (p < 0.014) but lower in its overall appeal (p < 0.0001). The "most preferred form to be prescribed" was DPI at 47.5% followed by non-CFC at 32.5% and CFC MDI at 20.1%. Concerning the ease of use among the three forms of test products, 59.9% of the patients indicated "no difference". Adverse events were mild and occurred in only 8.2%. In conclusion, patients' preference and sensory perception among the three forms of inhalers were comparable except that the CFC MDI was significantly less irritating but lower in its overall appeal. DPI was the most preferred and easiest form to use but also the most expensive. Taking public health into consideration, a non-CFC MDI with a similar market price to the CFC MDI would be the obvious choice in a strategic plan to phase out CFC MDIs with the least difficulty to the consumers.

Short-term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydrofluoroalkane-134a.

Inhaled beclomethasone dipropionate (BDP) with the propellant hydrofluoroalkane-134a (HFA) has been designed to be equivalent in terms of safety to chlorofluorocarbon (CFC)-formulated metered dose inhalers (MDI). The aim was to assess whether BDP HFA MDI 100 microg twice daily was equivalent to BDP CFC MDI 100 microg twice daily in terms of effects on short-term lower leg growth rate (LLGR) and measures of hypothalamic-pituitary-adrenal (HPA) function. The study consisted of a randomized double-blind cross-over trial with three active, a run-in and two wash-out periods each consisting of 2 wk. The place of study was a secondary referral outpatient clinic. The subjects involved were 14 boys and 10 girls with asthma, aged 7-12 yr. They were all administered BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily. The outcome measures included LLGR and 24-h urine-free cortisol (UFC) and total cortisol metabolites (TCM). Mean (SD) LLGR during run-in and BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily periods were 0.43 (0.23), 0.09 (0.29), 0.10 (0.45) and 0.08 (0.27) mm/wk. The one-sided 97.5% confidence interval for the difference in LLGR between BDP HFA 100 microg and BDP CFC 100 microg was 0.24, thus, below the predefined criterion of 0.20 mm/week. Inter-period comparisons of active treatments showed no differences between means of LLGR, UFC or TCM. Though non-inferiority between BDP HFA and CFC 100 microg twice daily in terms of effects on LLGR was not found, equivalence was suggested by comparisons of LLGR during run-in and active treatments and by HPA function measures.

Prolonged respiratory symptoms caused by thermal degradation products of freons.

OBJECTIVES: The chlorofluorocarbons (CFC) used in refrigeration systems decompose on heating and produce substances that are highly irritating to the airways (eg, chlorine, carbonyl fluoride, and hydrogen fluoride). This study examined persistent respiratory symptoms among several workers exposed to thermal decomposition products of CFC. METHODS: Seven patients with respiratory symptoms caused by inadvertent exposure to thermal decomposition products of CFC in a restaurant kitchen or during refrigerator repair were studied with the use of spirometry, peak flow follow-up, and histamine challenge tests. Three patients also underwent bronchoscopy and bronchoalveolar lavage. RESULTS: In five of the cases, cough or dyspnea lasted longer than 1 month; for three of the five, the symptoms lasted more than 4 years. Three cases showed increased bronchial hyperreactivity, and two of the three had increased diurnal peak flow variation. Three patients fulfilled the criteria for acute irritant-induced asthma or reactive airway dysfunction syndrome. One case exhibited bronchiolitis while, for the other six, the clinical picture was consistent with bronchitis. CONCLUSIONS: The studied cases indicate that the thermal decomposition products of CFC used in refrigerators may cause irritant-induced airway diseases of long duration.

Inhalation of decomposed chlorodifluoromethane (freon-22) and myocardial infarction.

After exposure to decomposed chlorodifluoromethane (freon-22), a 65-year-old man developed respiratory symptoms such as cough, blood-stained sputum, and increasing dyspnea. Three weeks later, his family doctor diagnosed infectious bronchitis. Another week later he died due to myocardial infarction. The discussion focuses on an inflammatory process caused by the inhalation of decomposed freon and its possible association with myocardial infarction.

Occupational voice disorders due to workplace exposure to irritants--a review of the literature.

The medical literature contains relatively few examples of reports of voice disorders that could be attributed to chemical exposure at work. General medical conditions such as gastro-oesophageal reflux and the use of medication such as inhaled steroids are well-recognized causes of laryngitis, but the occupational causes are less well documented. This paper describes the results of a literature review looking at the reporting of cases of occupationally acquired voice disorders due to exposure to irritants in the workplace.

Deaths related to the inhalation of volatile substances in Texas: 1988-1998.

Analysis of death certificates in Texas from 1988 to 1998 showed that the characteristics of 144 Texans for whom inhalants were mentioned as a contributing cause of death are different from those Texans who report use of inhalants in surveys and from persons who died from inhalant abuse in Virginia. While Texas surveys show little difference in prevalence of use between white and Hispanic adolescents or between boys and girls, Texas death data indicate inhalant use is also a problem among adult white males. The mean age of decedents was 25.6 years (SD 9.8 years), and ages ranged from 8 to 62 years. There were 92% males, 81% whites, and 17% Hispanics. Of the death certificates, 35% mentioned Freon, and 25% mentioned chlorinated hydrocarbons. Of those with the mention of Freon, 42% were students (mean age 16.4 years), and 37% were mechanics, installers, and repairers (mean age 27.4 years), occupations in which Freon can be readily available. Of the chlorinated hydrocarbon deaths, 49% were students (mean age 17.5 years), and 51% were from other occupations (mean age 27.4 years). Research on drug use and the workplace is not extensive, and the effects of inhalant intoxication can be a serious problem in the workplace. Prevention campaigns need to inform the public that inhalant abuse is not just a problem among youngsters, and intervention services for adult abusers should be provided within the context of employee assistance programs.

Human safety and pharmacokinetics of the CFC alternative propellants HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3, 3-heptafluoropropane) following whole-body exposure.

HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3, 3-heptafluoropropane) are used to replace chlorofluorocarbons (CFCs) in refrigerant and aerosol applications, including medical use in metered-dose inhalers. Production and consumption of CFCs are being phased out under the Montreal Protocol on Substances that Deplete the Ozone Layer. The safety and pharmacokinetics of HFC 134a and HFC 227 were assessed in two separate double-blind studies. Each HFC (hydrofluorocarbon) was administered via whole-body exposure as a vapor to eight (four male and four female) healthy volunteers. Volunteers were exposed, once weekly for 1 h, first to air and then to ascending concentrations of HFC (1000, 2000, 4000, and 8000 parts per million (ppm)), interspersed with a second air exposure and two CFC 12 (dichlorodifluoromethane) exposures (1000 and 4000 ppm). Comparison of either HFC 134a or HFC 227 to CFC 12 or air gave no clinically significant results for any of the measured laboratory parameters. There were no notable adverse events, there was no evidence of effects on the central nervous system, and there were no symptoms of upper respiratory tract irritation. HFC 134a, HFC 227, and CFC 12 blood concentrations increased rapidly and in an exposure-concentration-dependent manner, although not strictly proportionally, and approached steady state. Maximum blood concentrations (C(max)) tended to be higher in males than females; in the HFC 227 study, these were statistically significantly (P < 0. 05) higher in males for each HFC 227 and CFC 12 exposure level. In the HFC 134a study, the gender difference in C(max) was only statistically significant (P < 0.05) for CFC 12 at 4000 ppm and HFC 134a at 8000 ppm. Following the end of exposure, blood concentrations declined rapidly, predominantly biphasically and independent of exposure concentration. For the HFC 134a study, the t(1/2)alpha (alpha elimination half-life) was short for both CFC 12 and HFC 134a (<11 min). The t(1/2)beta (beta elimination half-life) across all exposure concentrations was a mean of 36 and 42 min for CFC 12 and HFC 134a, respectively. Mean residence time (MRT) was an overall mean of 42 and 44 min for CFC 12 and HFC 134a, respectively. In the HFC 227 study, t(1/2)alpha for both CFC 12 and HFC 227, at each exposure level, was short (<9 min) and tended to be lower in males than females. For CFC 12 mean t(1/2)beta ranged from 23 to 43 min and for HFC 227 the mean range was 19-92 min. The values tended to be lower for females than males for HFC 227. For both CFC 12 and HFC 227, MRT was statistically significantly lower (P < 0.05) in males than females and independent of exposure concentration. For CFC 12, MRT was a mean of 37 and 45 min for males and females, respectively, and for HFC 227 MRT was a mean of 36 and 42 min, respectively. Exposure of healthy volunteers to exposure levels up to 8000 ppm HFC 134a, 8000 ppm HFC 227, and 4000 ppm CFC 12 did not result in any adverse effects on pulse, blood pressure, electrocardiogram, or lung function.

Use of a job-exposure matrix to assess occupational exposures in relation to birth defects.

Accurate exposure assessment remains a challenge in occupational epidemiology. We evaluated one approach, use of a job-exposure matrix (JEM), by applying the National Institute for Occupational Safety and Health (NIOSH) JEM to a large case-control birth defects study that included parental occupation information. We investigated the JEM exposure predictions in several ways and found that for a substantial proportion of the parents in the birth defects study, the JEM yielded either no exposure data or nonsense predictions. Among exposure predictions that were plausible, most were of low probability. The high probability exposure predictions were statistically unstable, and neither low nor high probability exposure predictions were reliable. There was considerable discrepancy between the JEM predictions and expert assessments for five exposures of interest. Application of the NIOSH JEM to the birth defects study database (and probably other databases as well) does not provide a useful means of assessing occupational exposures.

Reactive airways dysfunction syndrome following exposure to a fluorocarbon.

This report describes the case of a 43-yr-old male who developed reactive airways dysfunction syndrome after exposure to a high level of bromotrifluoromethane (CF3Br, Halon 1301), a fluorocarbon widely used in automatic fire extinguishing systems. The patient was a previously healthy, nonatopic male, who developed wheezing and intermittent and reversible obstructive ventilatory impairment starting immediately after a large accidental nonfire-related release of CF3Br in a confined space.

Comparison of six respirator fit-test methods with an actual measurement of exposure in a simulated health care environment: Part III--Validation.

This article, the last in a series of three, describes the validation phase of a study conducted to test the correlation of respirator fit factors to the subject's actual exposure using biological sampling. The study consisted of three phases: protocol development, method comparison testing, and validation. Six quantitative fit-test methods were evaluated in the method comparison testing phase. The two fit methods with the highest correlation with the wearers' measured exposure were a corn oil method (R2 = 0.81) and an ambient aerosol method (R2 = 0.78). Because the ambient aerosol method is more commonly used in the workplace, it was selected for further analysis. In this validation phase, the fit factors measured during the ambient aerosol fit-test were used to calculate the exposures to Freon-113 by using the model determined in the method comparison testing phase of the study. The actual Freon-113 exposures were then measured and compared with the predicted exposures. The results verified that the ambient aerosol method fit factors are highly correlated to the total Freon-113 exposure dose and thus that the model had a predictive ability.

Trihalomethanes in public water supplies and adverse birth outcomes.

We conducted a retrospective cohort study to evaluate the relation between the level of total trihalomethanes in drinking water and adverse birth outcomes. The study population comprised women residing in an area with municipal surface water who had a singleton birth in Nova Scotia between January 1, 1988, and December 31, 1995, or a pregnancy termination for a major fetal anomaly. We found little association between trihalomethane level and the outcomes related to fetal weight or gestational age, but we found an elevated relative risk for stillbirths for average trihalomethane levels during pregnancy of 100 microg/liter or greater (adjusted relative risk = 1.66; 95% confidence interval = 1.09-2.52) relative to women exposed to trihalomethane levels of 0-49 microg/liter. We saw little evidence of an elevated prevalence or dose-response pattern for congenital anomalies, with the possible exception of chromosomal abnormalities (adjusted prevalence ratio = 1.38 and 95% confidence interval = 0.73-2.59 for women exposed to trihalomethane levels of 100 microg/liter or greater).

Switching patients with asthma from chlorofluorocarbon (CFC) albuterol to hydrofluoroalkane-134a (HFA) albuterol.

Chlorofluorocarbon (CFC) propellants deplete stratospheric ozone. Production and use of CFCs, except for certain critical exemptions, has been prohibited by the Montreal Protocol. Use of CFCs as propellants in metered-dose inhalers (MDIs) is still allowed, but the U.S. Food and Drug Administration is planning the transition to alternative propellants for use in MDIs. Hydrofluoroalkane-134a (HFA), a non-ozone-depleting propellant, has been used to reformulate albuterol (HFA albuterol). This study evaluates whether comparable safety and efficacy continues for 12 weeks after patients with asthma are switched from CFC albuterol to HFA albuterol. Patients with asthma stabilized on CFC albuterol during a 12-week safety and efficacy trial were randomized to either continue receiving CFC albuterol or to be switched to receive HFA albuterol in a yearlong safety and efficacy trial. Safety and efficacy were compared over the first 12 weeks of the yearlong trial between patients who had remained on CFC albuterol and those who had been switched to HFA albuterol. Bronchodilator efficacy was evaluated by serial spirometry for 6 hr after the patients self-administered the study drug in the clinic. Safety was assessed by measuring changes in pulse rate, blood pressure, and electrocardiogram (ECG) intervals after dosing with study drug, monitoring adverse events, and performing prestudy and poststudy laboratory testing and physical examinations. No significant differences in bronchodilator efficacy between the patients continuing to receive CFC albuterol and those switched to HFA albuterol were found in the 12 weeks after the switch. No differences between the two products were found for changes in pulse rate, blood pressure, and ECG intervals. Adverse event profiles were similar for the two products, except the patients remaining on CFC albuterol reported increased asthma symptoms and rhinitis significantly more often than the patients switched to HFA albuterol. No clinically meaningful changes in laboratory tests or physical examinations were found in either treatment group. Patients with asthma switched from CFC albuterol to HFA albuterol receive comparable bronchodilation with a similar safety profile as those continuing to receive CFC albuterol.

Comparison of six respirator fit-test methods with an actual measurement of exposure in a simulated health care environment: Part I--Protocol development.

Quantitative fit tests (QNFT) have been assumed to be predictive of the protection respirators would provide to a wearer in the workplace. Workplace studies have consistently found no correlation between quantitative fit factors and workplace protection factors. This article is the first in a series of three describing a study designed to compare the fit factors from six QNFT methods against the actual dose of 1,1,2 trichloro-1,2,2 trifluoroethane (Freon-113) received under the same laboratory conditions. Five preliminary studies conducted to develop the protocol to assess the respirator wearer's dose through end-exhaled air analysis are described in this article: (1) chamber characterization, (2) end-exhaled air sampling, (3) skin absorption testing, (4) pharmacokinetic modeling, and (5) subject characterization. It was established that the concentration of corn oil aerosol and Freon-113 could be generated simultaneously in the chamber. It was ascertained that the optimum time to sample the exhaled breath was 30 minutes after the subject exited the chamber. It was also found that in a chamber concentration of 500 ppm, without any respiratory exposure, Freon-113 was still present in the end-exhaled air. This was attributed to skin absorption. The end-exhaled air of subjects exposed to 0.5, 3, 5, 25, 50, and 100 ppm (30 minute time-weighted average) of Freon-113 was evaluated at 30 minutes postexposure. This characterization was then used to predict the actual dose of Freon-113 received during the method comparison and validation testing to be described in subsequent articles.

Comparison of six respirator fit-test methods with an actual measurement of exposure in a simulated health care environment: Part II--Method comparison testing.

This article, the second in a series of three, describes the method comparison testing portion of a study conducted to compare the fit factors from six quantitative fit-tests (QNFT) with a measure of a respirator wearer's actual exposure assessed by end-exhaled air analysis for 1,1,2-trichloro-1,2,2-trifluoroethane (Freon-113) under the same conditions. The six QNFT methods were (1) continuous low flow, flush probe; (2) continuous high flow, deep probe (CHD); (3) exhalation valve discharge (EVD); (4) controlled negative pressure; (5) 10-minute Ambient Aerosol 1 (AA1); and (6) 30-minute Ambient Aerosol 2. The first three methods utilized corn oil and a forward light scattering photometer. The last two methods used the TSI Portacount. Respirators used in the study were both disposable and elastomeric organic vapor/high efficiency half-masks. The characterization equations from the preliminary research (described previously) were used to determine the actual exposure to Freon-113 during the method comparison testing. The fit factors resulting from the QNFT methods were then individually correlated with the Freon-113 exposures using the coefficient of determination, R2. The lowest R2 value, 0.20, was found with the EVD method. The highest R2 values, 0.81 and 0.78, were associated, respectively, with the CHD and AA1 methods. This study suggests that some QNFT methods may be used to estimate actual respirator performance under laboratory conditions.

Facial injury and airway threat from inhalant abuse: a case report.

Fluorinated hydrocarbons cause toxicity in humans via their dysrhythmogenic potential and their local physical effects on the skin and mucous membranes. The former is generally the more life-threatening toxic consequence. We present a case of fluorinated hydrocarbon injury resulting from an intentional inhalation exposure that created facial frostbite, which threatened the patient's airway. The clinical range and management of these tissue-toxic effects are reviewed.

Trihalomethanes in drinking water and spontaneous abortion.

Trihalomethanes (chloroform, bromoform, bromodichloromethane, and chlorodibromomethane) are common contaminants of chlorinated drinking water. Although animal data indicate that these compounds may be reproductive toxicants, little information exists on their relation to spontaneous abortion in humans. We examined exposure to trihalomethanes and spontaneous abortion in a prospective study of 5,144 pregnant women in a prepaid health plan. Seventy-eight drinking water utilities provided concurrent trihalomethane sampling data. We calculated total trihalomethane levels by averaging all measurements taken by the subject's utility during her first trimester. We calculated exposures to individual trihalomethanes in an analogous manner. Women who drank > or = 5 glasses per day of cold tapwater containing > or = 75 micrograms per liter total trihalomethanes had an adjusted odds ratio (OR) of 1.8 for spontaneous abortion [95% confidence interval (CI) = 1.1-3.0]. Of the four individual trihalomethanes, only high bromodichloromethane exposure (consumption of > or = 5 glasses per day of cold tapwater containing > or = 18 micrograms per liter bromodichloromethane) was associated with spontaneous abortion both alone (adjusted OR = 2.0; 95% CI = 1.2-3.5) and after adjustment for the other trihalomethanes (adjusted OR = 3.0; 95% CI = 1.4-6.6).