Ethical issues of genetic susceptibility testing for occupational diseases: opinions of trainees in a high-risk job.

PURPOSE: Genetic research has opened up possibilities for identification of persons with an increased susceptibility for occupational disease. However, regulations considering the ethical issues that are inevitably associated with the use of genetic tests for susceptibility for occupational diseases are scarce. We investigated whether opinions of an intended stakeholder group, that is, student nurses, are sufficiently addressed by existing recommendations. METHODS: Attitudes and opinions of Dutch student nurses toward a genetic test for susceptibility to occupational contact eczema were studied in a qualitative setup using focus groups, interviews and electronic questionnaires. The results were compared with guidelines and recommendations extracted from the literature. RESULTS: Sixty-nine percent of the student nurses said they would partake in a genetic test for susceptibility to occupational contact eczema when available. Concerns were expressed regarding the difficulty of interpreting test results, the utility of the test result in practice and the necessity of genetic tests for non-severe diseases. For the issue of privacy and confidentiality, the students expressed few worries and much confidence. The existing guidelines largely covered the students' opinions. Still, the data emphasized the need for good individual risk communication both before and after testing, taking into account that the test concerns susceptibility. CONCLUSIONS: Comparing the students' statements with the issues addressed by the guidelines, we conclude that the guidelines should pay more attention to risk communication and practical advice accompanying the test results.

Loss-of-function polymorphisms in the filaggrin gene are associated with an increased susceptibility to chronic irritant contact dermatitis: a case-control study.

BACKGROUND: Polymorphisms in the filaggrin (FLG) gene, which result in loss of filaggrin production, may alter the skin barrier and are a well-known predisposing factor for atopic dermatitis. OBJECTIVES: As a compromised skin barrier and atopic dermatitis are risk factors for chronic irritant contact dermatitis (CICD), our objective was to determine whether polymorphisms in the FLG gene contribute towards susceptibility to occupational CICD. METHODS: In a case-control study, the FLG polymorphisms R501X and 2282del4 were determined in 296 patients with CICD. Two hundred and seventeen apprentices in vocational training for high-risk occupations for CICD were chosen as controls. Data on skin diseases and conditions were collected by dermatologists from patients and by means of questionnaires from controls. RESULTS: Heterozygotes for R501X and 2282del4, FLG null alleles, were more frequent among patients with CICD (12.5%) compared with controls (6.9%), resulting in an odds ratio of 1.91 (95% confidence interval 1.02-3.59). Among patients who were carriers of a FLG null allele, we found a higher lifetime prevalence of flexural eczema (62% vs. 46%; P = 0.04) and a higher atopy score (13 vs. 10 points; P = 0.05) compared with noncarriers. In the apprentice group, signs of dermatitis before the start of the vocational training were four times more prevalent in carriers (43%) than in noncarriers (10%; P < 0.001). CONCLUSIONS: Our study shows that FLG null alleles are associated with increased susceptibility to CICD; whether or not the FLG null allele is an independent risk factor needs further study.

Percutaneous penetration of sodium lauryl sulphate is increased in uninvolved skin of patients with atopic dermatitis compared with control subjects.

BACKGROUND: Involved regions of the skin in patients with atopic dermatitis (AD) have been shown to have higher transepidermal water loss (TEWL), indicating a compromised skin barrier. Whether uninvolved skin also has diminished barrier characteristics is controversial. OBJECTIVES: To study the penetration of sodium lauryl sulphate (SLS) into uninvolved skin of patients with AD compared with the skin of control subjects. METHODS: Percutaneous penetration was assessed using the tape stripping technique on the stratum corneum (SC). Twenty patients with AD and 20 healthy subjects were exposed to 1% SLS for 4 h on the mid-volar forearm. After the end of exposure the SC was removed by adhesive tape. The amount of SLS was determined in each consecutive strip. Fick's second law of diffusion was used to deduce the diffusivity and the partition coefficient of SLS between water and the SC. RESULTS: The SC thickness was similar in both groups; however, the TEWL was higher in patients with AD compared with that of the control group (mean+/-SD 8.4+/-4.3 and 6.3+/-2.0 g m-2 h-1, respectively). There was a correlation between SC thickness and TEWL in control subjects but no correlation was found in patients with AD. The diffusivity of SLS through uninvolved AD skin was higher compared with normal skin (mean+/-SD 12.7+/-5.8x10(-9) and 6.2+/-3.0x10(-9) cm-2 h-1, respectively), while the partition coefficient between SC and water was lower (mean+/-SD 137+/-64 and 196+/-107, respectively). CONCLUSIONS: The results show a different penetration profile of SLS into the SC of patients with AD compared with control subjects. This indicates that even noninvolved skin in patients with AD has altered barrier characteristics, emphasizing the importance of skin protection and prevention of skin contact with chemicals.

Variation in barrier impairment and inflammation of human skin as determined by sodium lauryl sulphate penetration rate.

BACKGROUND: Skin irritability after a brief exposure to the model skin irritant, sodium lauryl sulphate (SLS), is known to vary considerably between individuals. A difference in the skin barrier to SLS may contribute to this variation. To date, no human in vivo data have been available on SLS penetration into the skin. OBJECTIVES: We studied whether the SLS penetration rate into the stratum corneum (SC) is related to impairment of the water barrier function and inflammation of the skin. METHODS: The penetration of SLS into the SC was assessed using a noninvasive tape-stripping procedure in 20 volunteers after a 4-h exposure to 1% SLS. Additionally, the effect of a 24-h exposure to 1% SLS on the skin water barrier function was assessed by measuring the transepidermal water loss (TEWL). The accompanying inflammation was quantified by measuring erythema. RESULTS: The mean +/- SD diffusivity of SLS (D) and the SLS permeability coefficient (Kp) were 1.4 +/- 0.6 x 10(-8) cm2 h(-1) and 1.5 +/- 0.7 x 10(-3) cm h(-1), respectively. A multiple regression analysis showed that the baseline TEWL, SC thickness and SLS penetration parameters K (SC/water partition coefficient) and D clearly influenced the increase in TEWL after the 24-h irritation test (explained variance: r2 = 0.80). Change in erythema was mainly influenced by SC thickness. CONCLUSIONS: We found that variation in the barrier impairment and inflammation of human skin depends on the SLS penetration rate, which was mainly determined by SC thickness.

Skin reaction and recovery: a repeated sodium lauryl sulphate patch test vs. a 24-h patch test and tape stripping.

BACKGROUND: Little is known of the predictive value of methods to test an individual's susceptibility to acquiring occupational contact dermatitis. Recently, the recovery rate after induced irritation was suggested for this purpose. Although it is likely that repeated exposure to sodium lauryl sulphate (SLS) is preferable to a single application, there is little evidence to support this idea. Similarly, little is known about whether the outcome of a repeated SLS test can be predicted by a brief test. OBJECTIVES: We studied the relationship between the skin reaction after a repeated SLS test and two brief tests, devoting special attention to the recovery rate. METHODS: In 29 healthy volunteers, we measured transepidermal water loss (TEWL) and erythema after applying 0.03, 0.1 and 0.3% SLS for 6 h, 3 days per week, over a course of 3 weeks. The data were compared with the effects after applying 0.1, 0.3 and 1.0% SLS for 24 h and with 10 and 15 repetitions of tape stripping. RESULTS: A poor correlation was found between the repeated test and the brief SLS test, or tape stripping, when using an increase in TEWL (r = 0.04 and 0.26, respectively) or its recovery rate (r = - 0.01 and 0.42, respectively). CONCLUSIONS: We presume that in a repeated test of sufficient duration, additional mechanisms come into play that are absent in a brief test, e.g. an alteration in the thickness of the epidermis, with a resulting change in the permeability of SLS. When such an effect differs between subjects it could explain the lack of agreement between the acute and the repeated tests. At present, a brief irritation test will, in all likelihood, be unable to assess an individual's susceptibility to occupational contact dermatitis.

Routine diagnostic procedures for chronic encephalopathy induced by solvents: survey of experts.

OBJECTIVES: To study the routine diagnostic procedures used in different countries for chronic toxic encephalopathy (CTE) induced by solvents. METHODS: By means of a postal questionnaire selected international experts were asked about the methods they use to diagnose patients suspected of having CTE induced by solvents, the number of patients, entrance criteria, and the results of these diagnostic procedures. RESULTS: 18 Experts working in 18 diagnostic centres responded. Most of them agreed that a diagnostic procedure for CTE induced by solvents should contain an interview and neurological, physical, and neuropsychological examinations. However, the tests used were very different, as were the classifications for CTE. Depending on the institute, a diagnosis of CTE was made in 6%--70% of the referred patients. The proportion of patients with CTE stage I ranged from 0% to 33%, stage II from 5% to 100%, and stage III from 0% to 95%. CONCLUSION: The intentions of the two 1985 conferences that aimed at clarity and uniformity of diagnosis of CTE induced by solvents are far from reached. It is possible, now the conditions are more favourable, to aim at this important goal and recommend some refinement of the then proposed criteria.

Dermal absorption of neat liquid solvents on brief exposures in volunteers.

The dermal absorption of liquid 1,1,1-trichloroethane (111TRI), trichloroethene (TRI), tetrachloroethene (TETRA), toluene (TOL), and m-xylene (XYL) was studied in volunteers. The solvents were applied for 3 min on the volar forearm over an area of 27 cm2. An inhalation exposure with a known input rate served as a reference exposure. Using the linear system dynamics method, permeation rates were calculated from exhaled air concentration courses measured after both inhalation and dermal exposure. The permeation time courses of the solvents showed two different patterns. TRI, TOL, and 111TRI in three subjects showed fast increase in permeation, reaching maximal permeation rates a few minutes after initiation of exposure. Slower permeation was seen in the other three subjects exposed to 111TRI and in all subjects exposed to TETRA and XYL with the time of maximal permeation rates of 15-25 min. These differences in the permeation may partly be explained by the irritation of the skin observed in all subjects showing fast permeation kinetics. The flux into the skin averaged over the exposure period amounted to 56, 430, 69, 223, and 46 nmol/cm2/min for 111TRI, TRI, TETRA, TOL, and XYL, respectively. Comparing the dermal uptake with the respiratory uptake at the TLV, all solvents showed substantial skin absorption, although at present only TOL has a skin indication in the American Conference of Governmental Industrial Hygienists threshold limit value list.

[Solvent-induced chronic encephalopathy; the 'solvent team' project]. / Chronische encefalopathie door oplosmiddelen; het 'solventteam'-project.

Long-term exposure to organic solvents can result in damage of the central nervous system. The WHO recognises the following stages: organic affective syndrome, mild chronic toxic encephalopathy (CTE), and severe CTE. There is no golden standard for the diagnosis of CTE. Mild CTE is characterised by fatigue, mood disturbances, memory and attention disorders. In the Netherlands, a so-called 'solvent team' consisting of an occupational physician, a neurologist, a neuropsychologist and an occupational hygienist, assesses patients suspected of having CTE. The diagnostic procedure consists of three steps: (a) interview and blood tests, (b) the computer-based Neurobehavioral Evaluation System, and (c) assessment of an exposure index, neuropsychological investigation, and clinical neurological examination. In the period 1997-1999 approximately 250 patients were assessed yearly in the Netherlands; resulting in 50 diagnoses of mild CTE a year. The real incidence is most likely higher at present, but will decline due to diminished exposure to organic solvents.

Criteria for solvent-induced chronic toxic encephalopathy: a systematic review.

In 1985, a WHO Working Group presented diagnostic criteria and a classification for solvent-induced chronic toxic encephalopathy (CTE). In the same year, the "Workshop on neurobehavioral effects of solvents" in Raleigh, N.C., USA introduced a somewhat different classification for CTE. The objective of this review is to study the diagnostic procedures that are used to establish the diagnosis of CTE, and the extent to which the diagnostic criteria and classification of the WHO, and the classification of the Raleigh Working Group, are applied. A systematic search of studies on CTE was performed, and the diagnostic criteria and use of the WHO and Raleigh classifications were listed. We retrieved 30 original articles published in English from 1985 to 1998, in which CTE was diagnosed. Only two articles did not report the duration of solvent exposure. The type of solvent(s) involved was described in detail in four articles, poorly in 17 articles, and not at all in nine articles. Tests of general intelligence were used in 19 articles, and tests of both attention and mental flexibility and of learning and memory were used in 18 articles. Exclusion, by interview, of potentially confounding conditions, such as somatic diseases with central nervous effects and psychiatric diseases, was reported in 21 and 16 articles, respectively. In only six of the articles were both the WHO diagnostic criteria and the WHO or Raleigh classifications used. In the future, parameters of exposure, psychological test results, and use of medication that possibly affects psychological test results should always be described. We list some advantages and disadvantages of the Raleigh and WHO classifications. To aid inter-study comparisons, the diagnosis of CTE should be categorized and reported according to an internationally accepted classification.

Skin absorption of some vaporous solvents in volunteers.

OBJECTIVES: To determine the dermal absorption rates of vaporous 1,1,1-trichloroethane (111TRI), trichloroethene (TRI), tetrachloroethene (TETRA), hexane (HEX), toluene (TOL) and m-xylene (XYL) in humans. The determined absorption data were used for the validation of two published models for prediction of non-steady-state skin absorption. METHODS: Five volunteers were dermally exposed on an area of about 1,000 cm2 (forearm and hand) for 20 or 30 min. An inhalation exposure with a known dose rate served as a reference. Using the solvent concentrations in exhaled air, measured after both inhalation and dermal exposure, we calculated the maximum absorption rate into the blood, and the average absorption rates into the skin throughout the exposure, using the linear system dynamics method. RESULTS: The absorption rates into the skin, normalised for exposure concentration, amounted to 0.021 cm/h (111TRI), 0.049 cm/h (TRI), 0.054 cm/h (TETRA), 0.013 cm/h (HEX), 0.14 cm/h (TOL), and 0.12 cm/h (XYL). The maximum absorption rates into the blood ranged from 0.005 nmol/h for 111TRI and HEX to 0.050 nmol/hr for TOL. The ratios between the predicted and experimental values of the absorption rates into the skin ranged, for the model of Cleek and Bunge [4], from 0.3 (HEX) to 1.1 (TRI and TETRA), and for the model of Wilschut and Ten Berge [22], from 1.1 (HEX) to 4.7 (XYL). CONCLUSION: The linear system dynamics method allowed us to calculate not only the total amount absorbed by the skin but also the maximum absorption rate into the blood. The steady-state absorption rate, usually described by a permeability constant, will be below the absorption rate into the skin and above the maximum absorption rate into the blood. The skin absorption rates predicted by the models showed a good agreement with the experimental values. A comparison of the estimated whole-body skin uptake with the inhalatory uptake from the same atmosphere, revealed that the dermal uptake contributed from 0.1% (HEX) to 1% (TOL and XYL) to the total uptake.

Measurement and reduction of nitrous oxide in operating rooms.

In a program designed to lower exposure to anesthetic gases, nitrous oxide in the breathing zone of anesthesiologists was continuously monitored by means of a direct reading apparatus and a specially designed collar. Initially, the average concentration during anesthesia in intubated patients, determined in 30 operating rooms of seven hospitals, was 68 ppm. During mask anesthesia in children, it was 407 ppm (nine operating rooms, nine hospitals). The main hygienic measures were: a check of the anesthesia apparatus, improvement of the general ventilation in the operating room, and the application of a "double mask." With a combination of measures, the concentration during anesthesia in intubated patients was reduced from 61-90 ppm to 2-15 ppm. During mask anesthesia in children, the concentration decreased from 134-764 ppm to 9-42 ppm. The monitoring system used reveals important differences in the exposure during the separate phases of the anesthesia (induction, maintenance, and extubation). It also indicates which factors determine the exposure of the anesthetist and allows accurate determination of the personal exposure.

Environmental lead and renal effects in children.

The effect of lead on five renal-effect parameters was studied in 151 children (i.e., 3-6-y-olds) who resided at different distances from a lead smelter in Baia Mare, Romania. A relationship was found between concentration of lead in blood (mean +/- standard deviation: 342 +/- 224 microgram/l) and the activity of N-acetyl-beta-D-glucosaminidase in urine, as demonstrated by a 14% increase of N-acetyl-beta-D-glucosaminidase per 100 micrograms/l blood lead that was indicative of renal tubular damage. No relationship was found between blood lead level and the renal-effect parameters albumin, alpha-1-microglobulin, retinol binding protein, or alanine aminopeptidase in urine. Cadmium in blood was not elevated. It is well known that N-acetyl-beta-D-glucosaminidase is a sensitive parameter for renal effects, resulting from lead exposure in adults and from diabetes and nephrotoxic medicines in children. This study is the first to demonstrate an effect of environmental lead exposure on renal integrity in children.

Biomarkers of exposure versus parameters of external exposure; practical applications in estimating health risks.

To estimate the health risk of a specific part of the population due to an environmental factor, the exposure can be measured and consecutively evaluated by means of toxicity data from the literature. To facilitate the choice between parameters of external exposure (ExEx) versus biomarkers of exposure (BmEx), a guideline is proposed, which consists of eleven considerations. (1) Local effects (directly on airways, eyes or skin) usually require ExEx, whereas systemic effects call for BmEx. (2) Determination of the contribution of a specific, environmental source among multiple, e.g., non-environmental sources of a substance calls for ExEx. (3) The availability of a reliable exposure-response relationship for the effect considered and of a health-based limit value; theoretically a relationship based on BmEx can be more reliable. (4) The possibility to determine reliably the exposure data that are needed, depending on the time and duration of the sampling with respect to the pattern of the external exposure, on the number of samples, and the toxicokinetic properties. (5) Inconvenient route of entry points to BmEx. (6) The presence of a group at risk due to intake-related behaviour or toxicokinetics calls for BmEx. (7) In the case of non-specificity of BmEx due to other substances the increase or decrease of the effect predicting value should be evaluated. (8) Substantial probability of effects calls for BmEx. (9) Feasibility of sampling technique and reliability of the analysis. (10) Acceptance by the public points to BmEx. (11) Cost-effectiveness. Several examples illustrate this guideline.

Motor nerve refractory period distribution assessed by two techniques in diabetic polyneuropathy.

The techniques introduced by Kimura and Ingram et al. were applied to assess the distribution of motor refractory periods (DMRPs) in peroneal nerve fibres of 28 diabetics with symptoms indicating polyneuropathy and in 28 controls. Results were compared with conventional motor nerve conduction velocity (MNCV) and compound muscle action potential (CMAP) measurements. MRP95 and MRP90 (the 5% and 10% slowest recovering fibres) obtained with Ingram's technique were prolonged in the diabetic patients. In the 26 patients with a value of MRP95 and MNCV, a prolonged MRP95 and a decreased MNCV were found in 12 patients. Thus conventional MNCV had a sensitivity of 46% to detect neuropathy; addition of MRP95 obtained with Ingram's technique raised the sensitivity to 73%. Specificity was 100% in both cases. With Kimura's technique or with the fast recovering fibres in Ingram's technique, it was not possible to discriminate the patients from the controls. This study indicates that measurement of the DMRP with the technique introduced by Ingram et al. improves the electrophysiological diagnosis of diabetic polyneuropathy.

Effect of chronic mixed pesticide exposure on peripheral and autonomic nerve function.

In a cross-sectional study involving 131 flower bulb farmers (mean age = 43 y) and 67 well-matched controls, peripheral and autonomic nerve functions were examined. The study group had been exposed during a period of 20 y (standard deviation = 7) and applied a similar pesticide package. Lifetime cumulative exposure was estimated based on exposure levels for specific application methods and duration of exposure. Exposure-related decreased conduction velocities were found in the motor fibers of the median (-1.1 m/s) and peroneal (fast fibers: -1.2 m/s, slow fibers: -1.3 m/s) nerves, and in the sensory fibers of the median (-1.4 m/s) and sural (-0.9 m/s) nerves. In addition, the refractory period was determined and found to be increased in the sural and peroneal nerves. With regard to the autonomic nerve function, a decrease was found in resting sinus arrhythmia (-10%).

Verification of effects on the nervous system of low level occupational exposure to CS2.

Neurotoxic effects associated with long term low level occupational exposure to CS2 were reinvestigated four years after the initial study in the same group of workers. The second study concerned 44 exposed and 31 matched control workers. For both studies a personal cumulative exposure Ec was calculated based on function specific exposure levels and the occupational histories, which were carefully re-established. The exposed workers' average Ec was 192 and 213 ppm-years (first and second study respectively). Where possible the values of both data sets were used in a final combined analysis. Effects were found on the motor nerve conduction velocity of the fast (-0.9 m/s) and slow (-1.0 m/s) fibres of the peroneal nerve, the sensory nerve conduction velocity in the hand and arm segment of the median (-2.1 m/s) and ulnar (-1.3 m/s) nerves, and in the sural nerve (-1.3 m/s). An increased refractory period was found in the sural nerve (+ 0.2 ms, + 11%), but not in the peroneal nerve. For the autonomic nervous system an effect was found on the heart frequency response to isometric muscle contraction (-4.7 beats/min, -26%) and maximal forced respiration (-3.2 beats/min, -16%). This study shows the importance of a detailed evaluation of past exposure data. The reinvestigation enabled a more precise estimation of the effects of CS2, which is particularly desirable at around threshold exposure.

Nerve function in workers with long term exposure to trichloroethene.

Certain functions of the nervous system were examined in 31 printing workers (mean age 44) exposed to trichloroethene (mean duration 16 years) and 28 controls (mean age 45). In the sural nerve the conduction velocity (SNCV), response amplitude, and refractory period (SRP) were measured. The latencies of the masseter and the blink reflex were determined to test the trigeminal nerve. In the peroneal nerve the conduction velocity of fast and slow nerve fibres, the response amplitude, and the refractory period were determined. As a measure of autonomic nerve function the response of the heart rate was determined to isometric muscle contraction and deep breathing. Individual cumulative exposure was calculated on the basis of exposure levels in the past. The mean cumulative exposure of the exposed workers was 704 ppm x years. For the assessment of the exposure effect relation a multiple linear regression model was used. A slight reduction (-1.1 m/s) in the SNCV was found and a prolongation (0.4 ms) of the SRP (mean of the controls 1.95 ms). The latency of the masseter reflex (mean 10.4 ms) had increased (0.4 ms). With respect to the blink reflex no prolongation was found. No impairment was found in the functions of motor and autonomic nerves. This study shows that the refractory period may be a sensitive indicator of preclinical toxic neuropathies. Long term exposure to trichloroethene at threshold limit values (about 35 ppm) may slightly affect the trigeminal and sural nerves.