Trigger values for investigation of hormonal activity in drinking water and its sources using CALUX bioassays.

To screen for hormonal activity in water samples, highly sensitive in vitro CALUX bioassays are available which allow detection of estrogenic (ERα), androgenic (AR), progestagenic (PR), and glucocorticoid (GR) activities. This paper presents trigger values for the ERα, AR, PR, and GR CALUX bioassays for agonistic hormonal activities in (drinking) water, which define a level above which human health risk cannot be waived a priori and additional examination of specific endocrine activity may be warranted. The trigger values are based on 1) acceptable or tolerable daily intake (ADI/TDI) values of specific compounds, 2) pharmacokinetic factors defining their bioavailability, 3) estimations of the bioavailability of unknown compounds with equivalent hormonal activity, 4) relative endocrine potencies, and 5) physiological, and drinking water allocation factors. As a result, trigger values of 3.8ng 17ß-estradiol (E2)-equivalents (eq)/L, 11ng dihydrotestosterone (DHT)-eq/L, 21ng dexamethasone (DEX)-eq/L, and 333ng Org2058-eq/L were derived. Benchmark Quotient (BQ) values were derived by dividing hormonal activity in water samples by the derived trigger using the highest concentrations detected in a recent, limited screening of Dutch water samples, and were in the order of (value) AR (0.41)>ERα (0.13)>GR (0.06)>PR (0.04). The application of trigger values derived in the present study can help to judge measured agonistic hormonal activities in water samples using the CALUX bioassays and help to decide whether further examination of specific endocrine activity followed by a subsequent safety evaluation may be warranted, or whether concentrations of such activity are of low priority with respect to health concerns in the human population. For instance, at one specific drinking water production site ERα and AR (but no GR and PR) activities were detected in drinking water, however, these levels are at least a factor 83 smaller than the respective trigger values, and therefore no human health risks are to be expected from hormonal activity in Dutch drinking water from this site.

Health implications of PAH release from coated cast iron drinking water distribution systems in The Netherlands.

BACKGROUND: Coal tar and bitumen have been historically used to coat the insides of cast iron drinking water mains. Polycyclic aromatic hydrocarbons (PAHs) may leach from these coatings into the drinking water and form a potential health risk for humans. OBJECTIVE: We estimated the potential human cancer risk from PAHs in coated cast iron water mains. METHOD: In a Dutch nationwide study, we collected drinking water samples at 120 locations over a period of 17 days under various operational conditions, such as undisturbed operation, during flushing of pipes, and after a mains repair, and analyzed these samples for PAHs. We then estimated the health risk associated with an exposure scenario over a lifetime. RESULTS: During flushing, PAH levels frequently exceeded drinking water quality standards; after flushing, these levels dropped rapidly. After the repair of cast iron water mains, PAH levels exceeded the drinking water standards for up to 40 days in some locations. CONCLUSIONS: The estimated margin of exposure for PAH exposure through drinking water was > 10,000 for all 120 measurement locations, which suggests that PAH exposure through drinking water is of low concern for consumer health. However, factors that differ among water systems, such as the use of chlorination for disinfection, may influence PAH levels in other locations.

Screening and human health risk assessment of pharmaceuticals and their transformation products in Dutch surface waters and drinking water.

Numerous studies describe the presence of pharmaceuticals in the water cycle, while their transformation products are usually not included. In the current study 17 common pharmaceuticals and 9 transformation products were monitored in the Dutch waters, including surface waters, pre-treated surface waters, river bank filtrates, two groundwater samples affected by surface water and drinking waters. In these samples, 12 pharmaceuticals and 7 transformation products were present. Concentrations were generally highest in surface waters, intermediate in treated surface waters and river bank filtrates and lowest or not detected in produced drinking water. However, the concentrations of phenazone and its environmental transformation product AMPH were significantly higher in river bank filtrates, which is likely due to historical contamination. Fairly constant ratios were observed between concentrations of transformation products and parent pharmaceuticals. This might enable prediction of concentrations of transformation products from concentrations of parent pharmaceuticals. The toxicological relevance of the observed pharmaceuticals and transformation products was assessed by deriving (i) a substance specific provisional guideline value (pGLV) and (ii) a group pGLV for groups of related compounds were under the assumption of additivity of effects within each group. A substantial margin exists between the maximum summed concentrations of these compounds present in different water types and the derived (group) pGLVs. Based on the results of this limited screening campaign no adverse health effects of the studied compounds are expected in (sources of) drinking water in the Netherlands. The presence of transformation products with similar pharmacological activities and concentration levels as their parents illustrates the relevance of monitoring transformation products, and including these in risk assessment. More thorough monitoring yielding information on statistical uncertainty and variability in time and space, and research on possible synergistic effects of low concentration mixtures of compounds belonging to similar pharmacological classes require attention.

Polymorphisms in the interleukin-1 gene influence the stratum corneum interleukin-1 alpha concentration in uninvolved skin of patients with chronic irritant contact dermatitis.

BACKGROUND: Interleukin (IL)-1 alpha and its receptor antagonist IL-1 ra play a role in skin inflammation. Several polymorphisms in the IL1 gene cluster, coding for IL-1 alpha, IL-1 ra, and IL-1 beta, influence their protein expression. Within this cluster, strong linkage disequilibrium has been shown. OBJECTIVE: We studied the association between the polymorphisms IL1A-889 (C-->T) and IL1B-31 (T-->C) and the concentration of IL-1 alpha and IL-1 ra in the stratum corneum (SC). METHOD: In 124 patients with chronic irritant contact dermatitis, we genotyped the IL1A-889 and IL1B-31 polymorphisms and determined the amount of IL-1 alpha and IL-1 ra on tape strips obtained from uninvolved skin of the volar forearm. RESULTS: The SC IL-1 alpha concentration was 23% and 47% lower in subjects with IL1A-889 C/T genotype and T/T genotype, respectively, compared with wild-type genotype. In subjects with IL1B-31 C/C genotype, the IL-1 alpha concentration was 51% lower compared with C/T and T/T genotypes. The ratio IL-1 ra/IL-1 alpha increased twofold in IL1A-889 C/T genotype and threefold in T/T genotype compared with wild type. CONCLUSIONS: We have shown a clear effect of IL1 genotype on protein expression in the SC. This altered expression may be responsible for the interindividual differences in the inflammatory response of the skin.

Cytokine gene polymorphisms and susceptibility to chronic irritant contact dermatitis.

BACKGROUND: Cytokines play an important role in skin inflammation. OBJECTIVES: We determined whether polymorphisms in cytokine genes contribute to the occurrence of occupational chronic irritant contact dermatitis (CICD). METHODS: In a case-control study, 9 polymorphisms in the genes coding for interleukin (IL)-1 alpha, IL-1 beta, IL-8, IL-10, and tumour necrosis factor (TNF)-alpha were determined in 197 patients with CICD. 217 apprentices in vocational training for high-risk occupations for CICD served as controls. RESULTS: For all polymorphisms, no differences in genotype distributions were found between patients and controls. However, in patients with self-reported low levels of wet work and irritant exposure, more TNFA -308 variant genotypes (G/A and A/A) were present compared with those exposed to higher levels or controls, which indicates a TNFA-induced increase of susceptibility. In patients with TNFA -308 variant genotypes, the prevalence of flexural eczema was higher (48% and 57%) compared with that in patients presented with wild-type genotype (30%). Regarding IL1A -889, prevalence of symptoms of dermatitis was lower in apprentices with T/T or C/T genotype (32% and 36%) compared with wild-type genotype (54%, C/C). This indicates a protective effect of these variant alleles in acquiring hand dermatitis. CONCLUSIONS: This study provides evidence that some genetic variations alter susceptibility to (chronic) dermatitis. Knowledge of the impact of genetic differences on the risk of CICD is essential in predictive testing of individuals at risk.

Differential cytokine expression in skin after single and repeated irritation by sodium lauryl sulphate.

In vivo levels of cytokines and presence of neutrophils and eosinophils in skin irritation are not well known. Our objective was to get more insight in inflammatory mediators and markers involved in single and repeated skin irritation. We sampled epidermis-derived fluid using a novel technology that includes application of a negative pressure on the skin after creation of micropores in the stratum corneum by a laser. In nine volunteers, transdermal fluid was sampled after a single 4-h 10% sodium lauryl sulphate exposure and a repeated 3-week exposure (0.1% sodium lauryl sulphate). Twenty-seven cytokines were assessed by multiplex assay, and IL-1alpha, eosinophil cationic protein and myeloperoxidase by enzyme-linked immunosorbent assay. Levels of eosinophil cationic protein were increased after irritation and correlated with levels of myeloperoxidase. The levels of inflammatory mediators showed large interindividual differences in unexposed and exposed skin. Despite this variation, several mediators clearly showed increased levels: CC chemokine ligand (CCL)11, CXCL10 and vascular endothelial growth factor after both single and repeated exposure, IL-1alpha and basic fibroblast growth factor after single exposure and interleukin-1 receptor antagonist (IL-1RA) after repeated exposure. After repeated exposure, CCL5 and the ratio IL-1RA/IL-1alpha both increased compared with single exposure. We conclude that single and repeated irritation induces differential and concerted expression of various inflammatory mediators and markers.

Cytokines at different stratum corneum levels in normal and sodium lauryl sulphate-irritated skin.

BACKGROUND/PURPOSE: Cytokines play an important role in inflammatory and repair processes occurring in the skin. The objectives of this study were to determine the amounts of cytokines and protein isolated by tape stripping in the different layers of the stratum corneum (SC), and to compare normal skin with skin exposed in vivo to the irritant sodium lauryl sulphate (SLS). METHODS: In eight volunteers, we determined the amount of total and soluble protein and also interleukin-1alpha (IL-1alpha) in pooled tape strips obtained from the upper, intermediate and lower parts of the SC. Three different types of tape were compared (Diamond , D-squame or Sentega tape). In a separate study, 20 volunteers were repeatedly exposed to 0.1% SLS over a 3-week period. The amounts of IL-1alpha, IL-1RA and IL-8 in strips obtained from the three different SC levels of SLS-exposed skin were compared with an unexposed site. RESULTS: For normal skin, the amounts of soluble protein and IL-1alpha were similar for the three tapes. Diamond tape showed the highest yield of total protein. The total protein yield per strip decreased to lower SC levels, whereas soluble protein and IL-1alpha normalized by soluble protein did not change across the SC. After SLS induced skin irritation, IL-1alpha decreased and IL-1RA and IL-8 increased at increasing depth into the SC. CONCLUSIONS: Tape stripping is a suitable method to determine SC cytokine concentrations in human skin. With this technique, it is possible to study changes in cytokine concentrations at different SC layers after skin irritation.

Stratum corneum cytokines and skin irritation response to sodium lauryl sulfate.

Little is known about cytokines involved in chronic irritant contact dermatitis. Individual cytokine profiles might explain at least part of the differences in the individual response to irritation. Our objective was to investigate the relation between baseline stratum corneum (SC) cytokine levels and the skin response to a single and a repeated irritation test. This study also aimed to determine changes in SC cytokine levels after repeated irritation. Transepidermal water loss (TEWL) and erythema were measured in 20 volunteers after single 24-hr exposure to 1% sodium lauryl sulfate (SLS), and during and after repeated exposure to 0.1% SLS over a 3-week period. SC cytokine levels were measured from an unexposed skin site and from the repeatedly exposed site. Interleukin (IL)-1alpha decreased by 30% after repeated exposure, while IL-1RA increased 10-fold and IL-8 increased fourfold. Baseline IL-1RA and IL-8 values were predictors of TEWL and erythema after single exposure (r = 0.55-0.61). 6 subjects showed barrier recovery during repeated exposure. Baseline IL-1RA and IL-8 levels are likely to be indicators of higher skin irritability after single exposure to SLS. Barrier repair in some of the subjects might explain the lack of agreement between the TEWL response after single and repeated irritation.