In vitro predictions of skin absorption of caffeine, testosterone, and benzoic acid: a multi-centre comparison study.

To obtain better insight into the robustness of in vitro percutaneous absorption methodology, the intra- and inter-laboratory variation in this type of study was investigated in 10 European laboratories. To this purpose, the in vitro absorption of three compounds through human skin (9 laboratories) and rat skin (1 laboratory) was determined. The test materials were benzoic acid, caffeine, and testosterone, representing a range of different physico-chemical properties. All laboratories performed their studies according to a detailed protocol in which all experimental details were described and each laboratory performed at least three independent experiments for each test chemical. All laboratories assigned the absorption of benzoic acid through human skin, the highest ranking of the three compounds (overall mean flux of 16.54+/-11.87 microg/cm(2)/h). The absorption of caffeine and testosterone through human skin was similar, having overall mean maximum absorption rates of 2.24+/-1.43 microg/cm(2)/h and 1.63+/-1.94 microg/cm(2)/h, respectively. In 7 out of 9 laboratories, the maximum absorption rates of caffeine were ranked higher than testosterone. No differences were observed between the mean absorption through human skin and the one rat study for benzoic acid and testosterone. For caffeine the maximum absorption rate and the total penetration through rat skin were clearly higher than the mean value for human skin. When evaluating all data, it appeared that no consistent relation existed between the diffusion cell type and the absorption of the test compounds. Skin thickness only slightly influenced the absorption of benzoic acid and caffeine. In contrast, the maximum absorption rate of testosterone was clearly higher in the laboratories using thin, dermatomed skin membranes. Testosterone is the most lipophilic compound and showed also a higher presence in the skin membrane after 24 h than the two other compounds. The results of this study indicate that the in vitro methodology for assessing skin absorption is relatively robust. A major effort was made to standardize the study performance, but, unlike in a formal validation study, not all variables were controlled. The variation observed may be largely attributed to human variability in dermal absorption and the skin source. For the most lipophilic compound, testosterone, skin thickness proved to be a critical variable.

Color vision and occupational toluene exposure.

We examined the relationship between acquired color vision loss and exposure to toluene and total hydrocarbons among 125 male workers. Seventy-two toluene-exposed printers were compared with 34 workers from the same photogravure plant with ambient background exposure, and with 19 workers from a bookbinding plant located in the same town (nonexposed). Environmental mean toluene exposure level at workstation was estimated from individual 8-h sampling. Historic exposure data from the last 30 years were used to construct two cumulative exposure indices, one for toluene and one for total hydrocarbons. Airborne toluene levels were overall lower than the current Threshold Limit Value (TLV) of 50 ppm. Color vision was assessed by the Lanthony D-15 desaturated panel. Color vision loss was quantitatively established by the Color Confusion Index (CCI) and classified by type of acquired dyschromatopsia according to Verriest's classification. CCI was positively related to current airborne toluene levels, and cumulative exposure indices for toluene and total hydrocarbons (.18< or =r< or =.35). Odds ratios of acquired dyschromatopsia were significant for current airborne toluene, toluene, and total hydrocarbon past exposure (1.27 [1.02-1.58], 1.21 [1.04-1.39], 1.15 [1.02-1.31], respectively). In conclusion, this study suggests that the Lanthony D-15 desaturated panel detects early neurotoxic effects among workers exposed to toluene.

Estimation of the percutaneous absorption of styrene in an industrial situation.

OBJECTIVE: This field study was designed to compare the level of styrene absorbed percutaneously with that absorbed by inhalation in a real situation in the fiberglass-reinforced polyester industry. METHODS: The study protocol consisted of comparisons of the patterns of urinary excretion of styrene metabolites by four groups of workers, all of whom performed the same task at the same time in the same workshop but wore the following different protective equipment: total protection with an insulating suit and mask, respiratory equipment only, percutaneous protection only, and no protection. RESULTS: The urinary excretion level of the group with total protection did not significantly differ from that of the group with respiratory protection only. CONCLUSIONS: Precutaneous absorption is not a particularly important pathway for styrene absorption during stratification work in the polyester industry. Completely insulating personal protective equipment provides no greater level of protection than does a respirator at positive pressure alone.

Cutaneous sensitization to some polyisocyanate prepolymers in guinea pigs.

Isocyanates are used extensively in the polyurethane industry. Pulmonary and dermal sensitization resulting from exposure to diisocyanates has frequently been reported, but the potential effects of polyisocyanates on health are less well known. Thus, since 1978, occupational exposure limits have been established for diisocyanates only. Nevertheless, respiratory diseases and dermatitis have been reported in the polyurethane industry after accidental isocyanate contact during spills or splashes. The aim of this experimental work was to assess the dermal hypersensitivity of guinea pigs to some polyisocyanate prepolymers by means of a well-conducted standard predictive Buehler test. Our results showed that dicyclohexylmethane 4,4'-diisocyanate (HMDI), toluylene 2,4-diisocyanate (TDI), TDI adduct triol, TDI isocyanurate, 1,6-hexamethylene diisocyanate (HDI), HDI isocyanurate, HDI biuret and isophorone diisocyanate (IPDI) induced dermal sensitization while IPDI isocyanurate did not. In conclusion, the dermal hypersensitivity of guinea pigs to some polyisocyanates was similar to those of their corresponding monomers except for IPDI isocyanurate, suggesting that the results from diisocyanate monomers could not be a valuable approach for the detection of the sensitization potency of the corresponding prepolymers.

Immunologic and renal markers among photogravure printers exposed to toluene.

OBJECTIVES: This study assessed immunologic and early renal effects of chronic toluene exposure. METHODS: In a longitudinal study of 92 printers and 74 referents, 145 subjects had pre- and poststudy samples of blood and urine taken for the following measurements: immunoglobulin E (IgE), antiglomerular basement membrane (anti-GBM) and antilaminin (anti-LAM) antibodies in blood; creatinine and beta2-microglobulin in blood and urine; and microalbumin, N-acetyl-b-D-glucosaminidase (NAG) and alanine-aminopeptidase in urine. Creatinine clearance was calculated according to the Cockroft-Gault formula. Eight-hour personal air samples were collected twice to assess present exposure to toluene. A job-exposure matrix was developed to estimate past cumulative exposure. Information about potential confounders was recorded by questionnaire. Multiple regression analysis was performed to study dose-effect relations adjusted for age and smoking. RESULTS: No subject was positive for anti-GBM antibodies, and only 12 were positive for anti-LAM. No relation was observed between the markers studied and present exposure to toluene except that creatinine clearance was higher among the exposed subjects than among the referents. A dose-response relation was observed between cumulative toluene exposure and both IgE and NAG excretion. No interaction was observed between hypertension and exposure, but the relationship with NAG did not persist when subjects with hypertension were excluded. Past or present exposure did not alter the 2-year trend of any marker studied. CONCLUSIONS: According to the results of this study, toluene at 50 ppm is not related to detectable renal dysfunction. The increased IgE levels associated with present and past exposure require further investigation.

Occupational exposure to solvents and hairy cell leukaemia.

OBJECTIVES: The role of occupational exposures in hairy cell leukaemia was investigated through a multicentre, hospital based, case-control study. This paper analyses the role of exposure to solvents other than benzene in hairy cell leukaemia. METHODS: The study included 226 male cases and 425 matched controls, exposure to solvents was evaluated by expert case by case review of the detailed data on occupational exposures generated by specific interviews. Also, exposure to solvents was evaluated with an independently constructed job exposure matrix (JEM). RESULTS: No association was found between hairy cell leukaemia and previous employment in a job exposed to solvents (odds ratio (OR) 0.9 95% confidence interval (95% CI) 0.6 to 1.3). ORs for the main occupational tasks exposed to solvents were around 1 and did not increase with the frequency or the duration of the tasks. No specific type of paint or glue was found to be significantly associated with hairy cell leukaemia. No association was found with exposure to solvents, taken as a whole, with either expert assessments or the JEM. No association was found with aromatic, chlorinated, or oxygenated subgroups of solvents. The ORs did not increase with the average intensity of exposure assessed by the experts, with the frequency of use, or with the duration of exposure. Finally, no association was found with non-occupational exposure to solvents. CONCLUSIONS: The study did not show any association between exposure to solvents and hairy cell leukaemia.

Assessment of exposure to carcinogenic N-nitrosamines in the rubber industry.

Exposures to volatile nitrosamines were measured at 24 rubber manufacturing plants from 1992 to 1995. A total of 709 exposure measurements were taken in general areas or personal breathing zones to estimate exposure according to production types (seals, joints, tyres, gloves, etc.) and production steps, from mixing to storage. Five different nitrosamines were identified. N-Nitrosodimethylamine is the most frequently encountered nitrosamine and represents the most important fraction of the total nitrosamine concentration measured in a given sample. This fact is consistent with the use of rubber additives containing corresponding amine precursors. One hundred and forty-one of the 709 values exceeded the German target value (TRK) of 2.5 micrograms/m3 for all nitrosamines present from rubber vulcanisation, the only available standard for occupational nitrosamine exposures. The salt bath curing process generates particularly high nitrosamine levels, 90% of the 96 measurements being over the TRK, with many values exceeding 20 micrograms/m3. The reasons why the TRK is exceeded are generally well identified. To reduce nitrosamine emission levels it would be advisable to eliminate nitrogen oxide sources, principally by using a process other than salt bath curing, and to develop different rubber stocks that do not contain secondary aliphatic amine functional groups ("safe amines").

Hairy cell leukaemia and occupational exposure to benzene.

OBJECTIVES: The role of occupational exposures in hairy cell leukaemia (HCL) was investigated through a multicentre, hospital based, case-control study. This paper analyses the role of exposure to benzene in HCL. METHODS: A population of 226 male cases of HCL and 425 matched controls were included in the study. Benzene exposure was evaluated by expert review of the detailed data on occupational exposures generated by case-control interviews. RESULTS: No association was found between HCL and employment in a job exposed to benzene (odds ratio (OR) 0.9 (95% confidence interval (95% CI) 0.6-1.3)). The sample included 125 subjects, 34 cases (15%), and 91 controls (21%) who had been exposed to benzene, as individually assessed by the experts, for at least one hour a month during one of their jobs. Benzene exposure was not associated with a risk of HCL (OR 0.8 (0.5-1.2)). No trend towards an increase in OR was detected for increasing exposures, the percentage of work time involving exposure to > 1 ppm, or the duration of exposure. No findings suggested a particular risk period, when the OR associated with the time since first or last exposure, or since the end of exposure, were examined. CONCLUSIONS: In conclusion, with the low exposures prevalent in the sample, the study did not show any association between benzene exposure and HCL.

[Glomerular nephropathies and exposure to organic solvents--a case-control study]. / Néphropathies glomérulaires et exposition aux solvants organiques-- Etude cas-témoins.

Several studies have suggested that exposure to organic solvents is associated with glomerular nephropathies (GN), but this relationship remains controversial. A case-control study of 298 biopsy-proven cases and 298 hospital controls, matched for year of birth, sex, origin, and place of residence, was conducted between 1989 and 1991 in five hospitals in the Paris area : 82 cases of membranous glomerulopathy were included ; 100, nephrotic syndrome with either minimal change nephropathy or focal and segmental hyalinosis (MCN/FSH); and 116, IgA nephropathy (IgA N). Subjects were interviewed about their lifelong occupational and non-occupational activities. Type, level, and duration of solvent exposure were assessed blind with respect to case-control status by two industrial hygienists. HLA phenotypes were determined. Among males, a clear association, which was not explained by social class, was observed between chronic renal failure and high exposure to solvents for both MCN/FSH (OR = 7.7, 95% CI 1.4-41.6) and IgA N (OR = 3.5, 95% CI 1.0-11.8). The odds ratios increased with duration of exposure. No relationship was observed between such exposure and GN cases with normal renal function. No evidence was found that the HLA phenotype plays a role in the solvent exposure-disease association. These results support the hypothesis of a causal relationship between high solvent exposure, which concerned 15% of the males in this study, and the development of GN with chronic renal failure.

Organic solvent exposure may increase the risk of glomerular nephropathies with chronic renal failure.

BACKGROUND: Several studies have suggested that exposure to organic solvents is associated with glomerular nephropathies (GN), but this relationship remains controversial. METHODS: A case-control study of 298 biopsy-proven cases and 298 hospital controls, matched for year of birth, sex, origin, and place of residence, was conducted between 1989 and 1991 in five hospitals in the Paris area: 82 cases of membranous glomerulopathy were included; 100, nephrotic syndrome with either minimal change nephropathy or focal and segmental hyalinosis (MCN/FSH); and 116, IgA nephropathy (IgA N). Subjects were interviewed about their lifelong occupational and non-occupational activities. A 'blind' assessment of type, level, and duration of solvent exposure was carried out by two industrial hygienists. Human leucocyte antigen (HLA) phenotypes were determined. RESULTS: Among males, a clear association, which was not explained by social class, was observed between chronic renal failure and high exposure to solvents for both MCN/FSH (OR = 7.7, 95% CI: 1.4-41.6) and IgA N (OR = 3.5, 95% CI: 1.0-11.8). The odds ratios increased with duration of exposure. No relationship was observed between such exposure and GN cases with normal renal function. No evidence was found that the HLA phenotype plays a role in the association between solvent exposure and the disease. CONCLUSIONS: These results support the hypothesis of a causal relationship between high solvent exposure, which concerned 15% of the males in this study, and the development of GN with chronic renal failure.

Occupational exposure to polycyclic aromatic hydrocarbons and the risk of bladder cancer: a French case-control study.

BACKGROUND: The risk of bladder cancer has been shown to be increased in occupations which are likely to involve exposure to polycyclic aromatic hydrocarbons (PAH), but up to now, most studies have considered this exposure in terms of job title. METHODS: A hospital-based case-control study of 658 male cases of bladder cancer and 658 male controls was carried out in five areas of France from 1984 to 1987. For each subject, occupational exposure to PAH was assessed from questionnaires by an expert according to a semi-quantitative index of exposure. RESULTS: The overall odds ratio for PAH exposure, adjusted for smoking, coffee drinking and occupational exposure to aromatic amines was estimated at 1.3 (95% CI: 1.0-1.7, P < 0.05). A slight but clear dose-response relationship was observed, and the trend remained significant after adjustment for cumulative smoking, with odds ratios of 1.2 (95% CI: 0.9-1.7), 1.4 (95% CI: 0.9-2.2) and 1.8 (95% CI: 0.8-3.9) for low, medium and high average exposures respectively compared to subjects unexposed to PAH (P for trend < 0.05). Moreover, the association between bladder cancer and PAH exposure was also investigated in a category of smokers homogeneous with respect to their tobacco consumption. In this heavy-smoker group, a stronger association with PAH was detected. CONCLUSIONS: These results support the hypothesis of a causal relationship between occupational exposure to PAH and bladder cancer risk.

[Exposure of urban bus drivers to traffic pollution]. / Exposition des conducteurs de bus urbains aux polluants de la circulation automobile.

Two measurement campaigns aimed at measuring the air pollutant emissions of vehicles (carbon monoxide, nitrogen oxides, lead, benzo[a]pyrene and formaldehyde) have been carried out using on-board sampling or analysis equipment in public buses in two major French towns. The study had a double objective: (i) to assess the occupational exposure through pollutant measurements in the breathing zone of the drivers at their working posts, (ii) to compare the quality of the air sampled outside, either at the bus front (current position of the ventilation air intake), or on the vehicle roof. Carbon monoxide measurements were performed with several Ecolyser (electrochemical detection) standardized with a Mahiak Unor 6N infra-red non-dispersive analyser and nitrogen mono- and dioxide with AC 30 M Environment S.A. analysers (chemiluminescent detection), with a data-logger recording the '5-min weighted average concentrations'. Lead on dust was sampled on cellulose acetate or quartz filters and analysed by atomic absorption, benzo[a]pyrene (as a tracer of polynuclear hydrocarbons) on quartz filters and by HPLC/UV fluorescence detector and formaldehyde (as a tracer of aldehydes) on 2,4-DNPH-impregnated silicagel tubes by HPLC/UV. Recording and sampling were performed for 18 single and return routes in the center of Paris (for 1.5-2 h each) and for 25 routes in the center of Bordeaux (for 35-60 min). The results clearly indicate that the occupational exposures of urban bus drivers for the six pollutants are lower than the exposure limit values in the working place (French Labour Department or A.C.G.I.H. standards). In particular, levels for benzopyrene, associated with carcinogenic hazard, do not increase 5% of the standard from Russian origin (150 ng/m3). On the contrary, concentrations reached the levels recommended by international air quality standards (OMS, US or European standards) for carbon monoxide, nitrogen dioxide and lead. When CO mean concentration values by bus lines in the driver's breathing zone are compared with the measurement results provided for the same sample days by the Air-Parif control network (in Paris), or the Gertrude traffic management system (in Bordeaux), it may be assumed that they are at the level of the most polluted surveillance stations. The CO concentrations are significantly lower in the outdoor air coming from the roof than in that coming from the front of the bus, so that better indoor air quality at the driving post can be found with air intake from an upper than a lower part.

Occupational risks of bladder cancer in France: a multicentre case-control study.

The relationships between occupational risk factors in France and bladder cancer were assessed from a hospital-based case-control study conducted between 1984 and 1987 in five regions representing various industries, including mining, textile manufacture, metallurgy and the production of rubber and chemicals. The study concerned 765 cases (658 men and 107 women) and the same number of controls. Odds ratios (OR) adjusted for matching variables (age, place of residence and hospital), and tobacco smoking were estimated by unconditional logistic regression. A significantly increased risk of bladder cancer was observed among men employed in coal mining (OR = 2.42; 95% confidence interval (Cl) : 1.25-4.67) and the chemicals industry (OR = 2.36; 95% Cl : 1.23-4.53). Aircraft and ship's officers (OR = 11.8; 95% Cl : 1.46-95.7), managers (OR = 1.64; 95% Cl : 1.11-2.43) and street vendors (OR = 3.60; 95% Cl : 1.15-11.3) also had an increased risk. Among women, employment in the clothing industry was associated with a high OR (= 3.21; 95% Cl : 1.34-7.71). Assessment of individual exposures by a panel of industrial hygiene experts showed that significantly more cases than controls had been exposed to the following substances: chlorinated solvents (OR = 1.86; 95% Cl : 1.19-2.90), industrial oils and greases (OR = 1.44; 95% Cl : 1.10-1.89), welding fumes (OR = 1.40; 95% Cl : 0.98-2.01), coal dust (OR = 1.71; 95% Cl : 1.02-2.89) and metallic oxide dust (OR = 2.99; 95% Cl : 1.12-8.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Retrospective evaluation of occupational exposure to organic solvents: questionnaire and job exposure matrix.

Correct retrospective assignment of subjects to an exposure category is affected by a variety of problems: 1) lack of an objective lifetime measurement; 2) dependence upon the accuracy and thoroughness of the job description; 3) heavy reliance upon the knowledge of experts. The aim of the study was the quantification of the performance of a job exposure matrix (JEM) in evaluating solvent exposure, using expert judgements as the reference method. The sources of discrepancies between the two methods were analysed within the framework of two community-based case-control surveys. One included 765 cases of bladder cancer (BC) and 765 controls, the other 298 cases of glomerulonephritis (GN) and 298 controls. The JEM had been set up previously for a case-control study on laryngeal cancer and is based on 4000 discrete job titles. Comparison between the JEM and expert exposure evaluation was carried out for 2736 job periods in the BC study and 929 in the GN study. Categories of exposure for both experts and JEM were dichotomized, using different cutoff points for exposure and non-exposure. Prevalence of exposure as assessed by the experts was twice as high in the GN study (19%) as in the BC study (10%), showing the importance of the questionnaire design and of the inclusiveness of the definition of exposure. Sensitivity of the JEM vis-a-vis the experts was low (23-63%), whereas specificity was rather high (87-98%). The best concordance between the two methods was obtained with a specific dichotomy from the JEM and a narrow definition of exposure by the experts. Bias and loss of power resulting from JEM misclassifications were calculated with a theoretical population odds ratio of 3 and an exposure prevalence of 10%. If the experts' classification of the subjects according to exposure is assumed to be 100% correct, using the JEM led to a bias in estimating the odds ratio, ranging from 1.5 to 2.1, and to a loss of power equivalent to a reduction in the number of subjects by a factor of 5 to 10. Analysis of systematic discrepancies between exposure assessments of the experts and the JEM showed that they were clustered with some job categories and arose from different sources: 1) inadequate job descriptions, related to the codification system adopted and necessitating the gathering of information at the individual level; 2) true disagreements between JEM and experts regarding the definition of solvent exposure.(ABSTRACT TRUNCATED AT 400 WORDS)

The carcinogenic effect of a series of petroleum-derived oils on the skin of mice.

Six groups of 30 Swiss mice were treated by application to the skin in the dorsolumbar region two times a week for 12 months of a "white oil" and five samples of petroleum oils derived from the same "crude" (Middle East), which were collected in the same refinery at different stages of "solvent treatment" and which form a homogeneous series with increasing concentrations of polyaromatic hydrocarbons (PAH). The macroscopic and histopathologic examination of the animals (skin and organs) up to 18 months shows the following effects with respect to the 60-mouse control group: --a marked irritating effect for the "aromatic extract," the "distillate," and a "mixture" of intermediary concentration between "distillate" and "raffinate," --a definite tumorigenic effect on the skin (papillomas, kerato-acanthomas, squamous cell carcinomas, and fibrosarcomas) of the "aromatic extract" and the "distillate." The biological answer is in significant association with the PAH concentration of the samples, which is estimated by different analytical methods: viscosity index, percentage of aromatic carbon, "total PAH" according to a gravimetric method, and benzo[a]pyrene concentration.

N-nitrosodiethanolamine in antifreeze.

Carcinogenic N-nitrosodiethanolamine has been found at concentrations varying from 15 to 5700 mg/liter in several leading French brands of antifreeze. Moreover, mixtures of antifreezes which, separately, are innocuous, can form this nitrosamine which appears to arise from interaction of triethanolamine derivatives with sodium nitrite. It is recommended that sodium nitrite be abandoned as an anticorrosion additive.

Meat wrapper's asthma: identification of the causal agent.

Meat wrapper's asthma is a typical example of occupational asthma due to emissions from chemical products. The authors report three new cases due to the use of the now classic meat packaging techniques in supermarkets. The chemical agents involved were identified. Inhalation tests have been carried out in one patient with the complete wrappings, i.e. the PVC film and the price labels, and separate tests were performed with eight additives of the PVC film, and with phthalic anhydride and di-cyclohexylphthalate emitted from heated price labels. These tests incriminate two products: phthalic anhydride seems to be the principal causal agent and epoxidized soybean oil can be suspected as a secondary agent causing this occupational asthma.

Irritant dermatitis from diallylglycol carbonate monomer in the optical industry: clinical and experimental studies of cutaneous tolerance and chemical investigations.

The diallylglycol carbonate monomer causes dermatitis due to irritation in the optical industry. Cutaneous intolerance may effect as many as 70% of the exposed persons employed. Almost all control subjects who where patch-tested showed irritation at a 2% concentration. The histological effects were an acute oedema with inflammation of the papillary dermis, and diapedesis of neutrophil polymorphonuclear leukocytes. Experiments on animals confirmed the irritant nature of the product; in the rabbit, a single application produced irritation, but to a lesser degree than in humans. Tests for possible sensitizing effects in the guinea pig have given negative results. Chemical analysis of the monomer revealed the presence of diallyl carbonate and acrolein. Allyl alcohol was detected in only one case. Patch tests were carried out in a group of control subjects with acrolein, diallyl carbonate and allyl alcohol. The histological appearance of the lesions caused by acrolein was quite different from that due to diallyglycol carbonate. It is probable that the irritant is the diallylglycol carbonate monomer itself.