[Risk evaluation of carcinogens and their threshold levels, part III].
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Animals↗
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[A regulatory view on the article: Risk evaluation of carcinogens and their threshold levels, part I-III].
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Benchmarking↗
A summary of two meta-analyses on neurobehavioural effects due to occupational lead exposure.
The conclusions from published results about neurotoxic effects of inorganic lead exposures <700 microg lead/l blood are contradictory at present. Effects measured by neurobehavioural methods are evaluated differently as far as recommendations for a Biological Exposure Index (BEI) of occupational lead exposure are concerned. Arguments against the German BEI of 400 microg/l were put forward in new publications, and discussion of the issues is the aim of this article. It summarizes two different meta-analytical reviews on neurobehavioural effects in order to show the main tendencies of 24 selected publications on the matter. Calculations on effect sizes are compiled for 12 tests analysed in two meta-analyses and of ten tests analysed in one of the meta-analyses. The survey of six tests of learning and memory gives hints on impairments measured with two tests, covering Logical Memory and Visual Reproduction. The survey of seven tests of attention and visuospatial information processing describes impairments in four tests, namely Simple Reaction, Attention Test d2, Block Design, and Picture Completion. The survey of four tests for psychomotor functions shows impairments for three tests, namely Santa Ana, Grooved Pegboard, and Eye-hand Coordination. These test results provide evidence for subtle deficits being associated with average blood lead levels between 370 and 520 microg/l. In evaluating the adversity of such effects it is concluded that the results of both meta-analytical reviews support the recommendation for the German BEI.
Cognition↗
A meta-analysis for neurobehavioural results due to occupational lead exposure with blood lead concentrations <70 microg/100 ml.
The size of performance effects caused by exposure to inorganic lead was determined by a meta-analytical procedure. Twenty-two studies covering exposure conditions of <70 microg/100 ml blood lead concentration were considered as to whether the methods of recording performance deficits were comparable. As a consequence of different test procedures and insufficient documented test results only 13 tests out of 12 studies could be included in the analysis. For the tests Block Design, Logical Memory and Santa Ana performance deficits were found, which may be interpreted as 'small' effects in accordance with a convention for evaluating effect sizes. For the example of Block Design it could be shown that these effects are nevertheless serious. The extent of the exposure related decrease of performance was comparable with those changes of performance which can be expected during aging of up to 20 years. Subsequently, a blood lead concentration of 70 microg/100 ml cannot be considered as a safe limit against long-term decreases of psychological performance.
Adult↗
Chemosensory irritation and the setting of occupational exposure limits.
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Dose-Response Relationship, Drug↗
Local effects in the respiratory tract: relevance of subjectively measured irritation for setting occupational exposure limits.
OBJECTIVES: Chemosensory effects of stimulation by a chemical can either be irritating (trigeminal stimulation) or odorous (olfactory stimulation) or both. For odorous irritants, a clear-cut distinction between odour and irritation is difficult to make. The differences in the lowest concentration found to be irritating to the respiratory tract in humans when compared to experimental animals has brought much debate in the process of setting occupational exposure limits (OELs) for such chemicals. In this paper it will be discussed as to how far subjectively measured sensory irritation threshold levels can be used to establish OELs. METHODS: Data on respiratory irritation of four odorous irritants were retrieved from public literature and discussed, viz. acetone, formaldehyde, furfural and sulphur dioxide. RESULTS: Objective measures of irritation yielded results that differed from subjective evaluations. Important factors modulating the reported levels of irritation and health symptoms include the perception of odour intensity, exposure history and the individual's bias to report irritation on the basis of his/her prejudice or knowledge of the compound. CONCLUSIONS: Subjective measures alone are less appropriate for establishing sensory irritation thresholds of odorous irritants and are, therefore, less suitable to establish OELs without supporting evidence. Objectively measured irritation in humans, the Alarie assay (an experimental animal test assessing the concentration that results in a 50% reduction of the breathing frequency) and repeated exposure studies in animals may be of help to study objective irritation. If subjective measurements are used to study sensory irritation, the study design should at least include: measurement of both incidence and severity determined at several concentrations, an appropriate (0 ppm) control condition, preferably a non-irritant odorant control exposure, validated questionnaires and correct concentration measurements.
Air Pollutants, Occupational↗
Setting occupational exposure limits in humans: contributions from the field of experimental psychology.
Psychophysical methods from the field of experimental psychology are evaluated for their utility in the derivation of occupational exposure limits (OELs) for volatile chemicals based on acute sensory irritation in humans. The lateralization threshold method, which involves the localization of trigeminal vapor to the stimulated nostril, is evaluated for its underlying assumptions, reliability and validity. Whole body exposures, on the other hand, which involve the controlled, ambient exposure of human subjects to the irritant at one or a series of concentrations for an extended period are also discussed. It is concluded that the single-organ psychophysical method is largely resistant to response bias is practical and economical. However, its reliability and validity need further assessment. Whole body exposures, while having enhanced ecological validity, are more prone to demand characteristics, response bias, and subject beliefs than the traditional psychophysical procedures. An approach that involves the exposure of only the most sensitive organs such as the eyes and nose, via a mask or facebox, could facilitate the administration and alternation of odorant/irritant stimuli over a wide range of concentrations while enhancing ecological validity.
Air Pollutants, Occupational↗
Time-resolved cutaneous absorption and permeation rates of methanol in human volunteers.
This paper reports on an experimental study of dermal exposure to neat methanol in human volunteers for the purposes of estimating percutaneous absorption rates, permeation kinetics, baseline (pre-exposure) levels of methanol in blood, and inter- and intrasubject variability. A total of 12 volunteers (seven men and five women) were exposed to methanol via one hand for durations of 0 to 16 min in a total of 65 sessions, making this the largest controlled study of percutaneous absorption for this common solvent. In each session, 14 blood samples were collected sequentially and analyzed for methanol. These data were used to derive absorption rates and delivery kinetics using a two compartment model that accounts for elimination and pre-exposure levels. The pre-exposure methanol concentration in blood was 1.7 +/- 0.9 mg 1(-1), and subjects had statistically different mean concentrations. The maximum methanol concentration in blood was reached 1.9 +/- 1.0 h after exposure. Delivery rates from skin into blood lagged exposure by 0.5 h, and methanol continued to enter the systemic circulation for 4 h following exposure. While in vitro studies have reported comparable lag times, the prolonged permeation or epidermal reservoir effect for such miscible solvents has not been previously measured. The mean derived absorption rate, 8.1 +/- 3.7 mg cm-2 h-1, is compatible with that found in the other in vivo study of methanol absorption. Both in vivo absorption rate estimates considerably exceed in vitro estimates. The maximum concentration of methanol in blood following an exposure to one hand lasting approximately 20 min is comparable to that reached following inhalational exposures at a methanol concentration of 200 ppm, the threshold limit value-time weighted average (TLV-TWA). While variability in blood concentrations and absorption rates approached a factor of two, differences between individuals were not statistically significant. The derived absorption and permeation rates provide information regarding kinetics and absorbed dose that can help to interpret biological monitoring data and confirm mathematical models of chemical permeation.
Adult↗
The exposure of healthy volunteers to 200 ppm 1,1,1-trichloroethane increases the concentration of proinflammatory cytokines in nasal secretions.
OBJECTIVES: Irritating effects of organic solvents have usually been measured by means of questionnaires. The aim of the present study was to evaluate the sensitivity of different methods of detecting subclinical irritating effects. METHODS: Twelve healthy, non-smoking students were exposed to 200 ppm and to 20 ppm 1,1,1-trichloroethane in an exposure chamber, using a crossover design. The amounts of interleukins (IL)-1beta, IL-6 and IL-8 and prostaglandin E(2) (PGE(2)) in nasal secretions were measured. Mucociliary transport time was determined with the saccharine test. Ciliary beat frequency of nasal epithelial cells was measured with video-interference contrast microscopy. Subjective symptoms were assessed by questionnaire. RESULTS: Concentrations of ILs were significantly elevated after exposure to 200 ppm 1,1,1-trichloroethane (IL-1beta 82.4 vs. 28.8 pg/ml (medians), P=0.003; IL-6 12.2 vs. 7.2 pg/ml, P=0. 01; IL-8 549 vs. 424 pg/ml, P=0.007), whereas the other parameters remained unchanged. CONCLUSION: The interleukins measured proved to be sensitive indicators of irritating effects of 1,1, 1-trichloroethane. The German threshold limit (MAK value) of 200 ppm 1,1,1-trichloroethane does not prevent the subclinical inflammation of nasal mucosa.
Adult↗
Assessment of outer hair cell function and blood antioxidant status of rabbits exposed to noise and metal welding fumes.
OBJECTIVES: To investigate the interaction between welding fumes and noise in causation of hearing impairment. METHODS: Groups of rabbits (n=6) were exposed to noise, welding fumes or combination of both prior to Distortion Product Otoacoustic-Emissions (DPOAEs) analysis. The function of outer hair cells (OHCs) was examined by DPOAE assessment over a broad range of frequencies. Variations in DPOAE amplitude were compared between control (n=6) and exposed (n=18) groups. RESULTS: The DPOAEs levels measured at different frequencies (1379-6299 Hz) were found to decrease significantly (P<0.05) in rabbits exposed to 110 dB sound pressure level (SPL) broadband noise (8h/day, 12 days). In rabbits, exposed to carbon-steel welding fumes alone (157 mg/m(3)), the threshold shift was limited to the high frequencies (2759-6299 Hz), whereas, mixed exposure to noise and fumes resulted in reduction of DPOAEs at all the frequencies. Changes in DPOAEs were associated with increased susceptibility of erythrocytes to oxidation (P<0.05). Exposure to noise or fumes alone or simultaneously, suppressed total antioxidant ability of plasma as measured by ferric reducing ability of plasma (FRAP). Noise alone or in combination with fumes resulted in depletion of blood glutathione (GSH). Despite suppression of FRAP in the exposed groups, GSH was found to remain unchanged due to welding fumes suggesting that antioxidants other than GSH are affected by toxicants present in metal welding fumes. CONCLUSION: Exposure to very high levels of welding fumes can increase noise-related effects on OHC function by extending hearing threshold shift to wide band frequencies.
Air Pollutants, Occupational↗
European union system for the evaluation of substances: the second version.
This publication presents major changes in the assessment of the risks of chemicals to human health and the environment as implemented in the second version of the European Union System for the Evaluation of Substances, EUSES 2.0. EUSES is a harmonised quantitative risk assessment tool for chemicals. It is the PC-implementation of the technical guidelines developed within the framework of EU chemical legislation for industrial chemicals and biocides. As such, it is designed to support decision making by risk managers in government and industry and to assist scientific institutions in the risk assessment for these substances. The development of EUSES 2.0 is a co-ordinated project of the European Chemicals Bureau, EU Member States and the European chemical industry. Several model concepts, the technical background and the user interface of EUSES have been improved considerably. Major changes in the environmental assessment such as the implementation of emission scenario documents for industrial chemicals and biocides, the addition of the marine risk assessment, the enhancement of the regional model to include global scales, and improvements in the secondary poisoning and environmental effects modelling will be discussed. The update of the human risk assessment module in EUSES focuses on the risk characterisation for both threshold and non-threshold substances with, among others, the introduction of assessment factors. The performance of EUSES is illustrated in an example showing the human and environmental risk assessment of a sanitation disinfectant for private use.
Animals↗
PREDICTOL: a computer program to determine the thermophysiological duration limited exposures in various climatic conditions.
PREDICTOL is a PC program used to determine the thermophysiological duration limited exposures (DLE) in humans, nude or clothed, submitted to various climatic conditions (hot and cold climates) at rest or during a physical exercise. DLE are determined following different standards of the International Standardization Organization (ISO), especially ISO 7933 for hot environment and ISO-TR 11079 for cold environment. The original aspect of this program is that it can be used whatever the climatic conditions. The program presents two modes: an educational interactive mode and a scenario mode. The educational interactive mode demonstrates the thermophysiological effects, expressed as DLE, of different parameter changes (temperature, humidity, wind speed, metabolic heat production by physical exercise, clothing insulation and water vapor permeability). The scenario mode determines DLE for given various linked sequences as encountered in occupational, military or even recreational activities, each sequence being characterized by its climatic conditions, physical activities performed and by physical clothing properties. DLE given by PREDICTOL are correlated to those obtained in various controlled climatic laboratory conditions (r = 0.86; P < 0.001). PREDICTOL is written in Visual Basic 6.0. A "help menu" is provided to explain the use of the program and give information concerning the equations used to calculate both the thermal balance and DLE.
Body Temperature Regulation↗
Thresholds of elicitation depend on induction conditions. Could low level exposure induce sub-clinical allergic states that are only elicited under the severe conditions of clinical diagnosis?
While numerous studies have examined dose/response relationships occurring in the experimental induction of contact allergic dermatitis, fewer have examined the effects of varying the doses of both induction and challenge. Recently published studies have however done this and they all show the same remarkable observation: the threshold of elicitation decreases as the doses used to induce the allergy increase. This has important implications. One is that it may be more complicated to determine clear threshold doses below which allergic responses are not seen. It is also proposed that normal exposure to weak allergens such as some fragrance materials may induce "sub-clinical" allergic states which will not be elicited under these same exposure conditions but which may become apparent under the more severe conditions of clinical diagnosis. This may explain why the prevalence of Patch test reactions to some fragrance materials is apparently increasing in the absence of any clearly documented "epidemic" of consumer complaints.
Allergens↗
Toward a definition of a threshold for harmless doses to the anal-sphincter region and the rectum.
PURPOSE: To investigate dysfunction caused by unwanted radiation to the anal-sphincter region and the rectum. METHODS AND MATERIALS: A questionnaire assessing bowel symptoms, sexual function, and urinary symptoms was sent to 72 patients with clinically localized prostatic adenocarcinoma treated by external beam radiation therapy at the Radiumhemmet, Karolinska Hospital, in Stockholm, Sweden, 2-4 years after treatment. The mean percentage dose-volume histograms for patients with and without the specific symptom were calculated. RESULTS: Of the 65 patients providing information, 9 reported fecal leakage, 10 blood and mucus in stools, 10 defecation urgency, and 7 diarrhea or loose stools. None of the 19 and 13 patients who received, respectively, a dose of > or =35 Gy to < or =60% or > or =40 Gy to < or =40% of the anal-sphincter region volume reported fecal leakage (p < 0.05). In dose-volume histograms, a statistically significant correlation was found between radiation to the anal-sphincter region and the risk of fecal leakage in the interval 45-55 Gy. There was also a statistically significant correlation between radiation to the rectum and the risk of defecation urgency and diarrhea or loose stools in the interval 25-42 Gy. No relationship was found between anatomic rectal wall volume and the investigated late effects. CONCLUSIONS: Although the limited data in this study prevent the definition of a conclusive threshold regarding volume and dose to the anal-sphincter region and untoward morbidity, it seems that careful monitoring of unnecessary irradiation to this area should be done because it can potentially help reduce the risk of adverse effects, such as fecal leakage. Future studies should pay more attention to the anal-sphincter region and help to more rigorously define its radiotherapeutic tolerance.
Aged↗
Substance prioritisation for the development of EU Acute Exposure Toxicity Thresholds (AETLs).
The aim of the EU Acute Exposure project, ACUTEX, is to develop a methodology for establishing European Acute Exposure Threshold Levels, EU AETLs, for toxic substances in relation to harm to people by inhalation. The development of AETLs is initially in the context of the risks of major accidents from chemical sites and in particular their regulation through the EU 'Seveso II' Directive. It is intended that AETLs can be used within Member States, where appropriate, to inform decisions on land-use planning and emergency planning. AETLs will not have a regulatory status. This paper describes: the selection of 21 preliminary substances to use as case studies in the development and testing of the AETL's methodology; and the development of a prioritisation methodology to inform initial substance selection for a possible further AETLs program. The work was based on consultation with experts drawn from EU major stakeholder groups. It included a Validation Exercise working with three Member States, which account for between approximately 40% and 50% of all EU Seveso II sites. From this Validation Exercise we infer that, if these three Member States are representative in terms of numbers of priority substances, then the number of EU higher priority substances for further AETLs development is unlikely to be much in excess of 50.
Environmental Exposure↗
The nervous system effects of occupational exposure to manganese--measured as respirable dust--in a South African manganese smelter.
OBJECTIVES: A major recent review of occupational exposure limits for manganese (Mn) has proposed a respirable dust level of 0.1 mg/m3. There is, however, no theoretical basis for using this exposure metric to estimate the systemic effects of Mn, and little in the way of empirical data relating respirable Mn to neurobehavioural and other non-pulmonary effects. Cross-sectional data from a study showing few and unconvincing neurobehavioural effects of inhalable dust in Mn smelter workers published just prior to this review were reanalyzed here using respirable Mn. The hypotheses tested were that respirable Mn exposure is a more appropriate predictor of neurobehavioural effects than inhalable Mn where such effects exist, and that there should be no observed effects at respirable dust levels below 0.1 mg/m3. METHODS: Five hundred and nine production workers and 67 external referents were studied. Exposure measures from personal sampling included the Mn content of respirable dust as a concentration-time integrated cumulative exposure index (CEI) and as average intensity (INT) over a working lifetime. Neurobehavioural endpoints included items from the Swedish nervous system questionnaire (Q16), World Health Organisation neurobehavioural core test battery (WHO NCTB), Swedish performance evaluation system (SPES), Luria-Nebraska (LN), and Danish Product Development (DPD) test batteries, and a brief clinical examination. RESULTS: The median respirable Mn exposure was 0.058 mg/m3 (range=0-0.51; IQR=0.02-0.16) amongst the exposed, with 30% having average intensities above the proposed 0.1 mg/m3 and 44% above the proposed supplemental limit of 0.5 mg/m3 inhalable dust. As in the study of inhalable Mn effects, there were few respirable Mn effects showing clear continuity of response with increasing exposure. CONCLUSION: These data did not provide empirical support for a respirable, as opposed to an inhalable, dust metric being more sensitive in the identification of Mn effects. Neither metric showed convincing effects within the exposure range studied. Further study is needed to determine a threshold for respirable Mn effects, if such exist, and to verify our findings.
Adult↗
NTP-CERHR Expert Panel report on the reproductive and developmental toxicity of 1-bromopropane.
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Animals↗
Experimental and mathematical modeling methods for the investigation of toxicological interactions.
While procedures have been developed and used for many years to assess risk and determine acceptable exposure levels to individual chemicals, most cases of environmental contamination can result in concurrent or sequential exposure to more than one chemical. Toxicological predictions of such combinations must be based on an understanding of the mechanisms of action and interaction of the components of the mixtures. Statistical and experimental methods test the existence of toxicological interactions in a mixture. However, these methods are limited to experimental data ranges for which they are derived, in addition to limitations caused by response differences from experimental animals to humans. Empirical methods such as isobolograms, median-effect principle and response surface methodology (RSM) are based on statistical experimental design and regression of data. For that reason, the predicted response surfaces can be used for extrapolation across dose regions where interaction mechanisms are not anticipated to change. In general, using these methods for predictions can be problematic without including biologically based mechanistic descriptions that can account for dose and species differences. Mechanistically based models, such as physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models, include explicit descriptions of interaction mechanisms which are related to target tissues levels. These models include dose-dependent mechanistic hypotheses of toxicological interactions which can be tested by model-directed experimental design and used to identify dose regions where interactions are not significant.
Animals↗