New aspects in deriving health-based guidance values for bromate in swimming pool water.

Bromate, classified as a EU CLP 1B carcinogen, is a typical by-product of the disinfection of drinking and swimming pool water. The aim of this study was (a) to provide data on the occurrence of bromate in pool water, (b) to re-evaluate the carcinogenic MOA of bromate in the light of existing data, (c) to assess the possible exposure to bromate via swimming pool water and (d) to inform the derivation of cancer risk-related bromate concentrations in swimming pool water. Measurements from monitoring analysis of 229 samples showed bromate concentrations in seawater pools up to 34 mg/L. A comprehensive non-systematic literature search was done and the quality of the studies on genotoxicity and carcinogenicity was assessed by Klimisch criteria (Klimisch et al., Regul Toxicol Pharmacol 25:1-5, 1997) and SciRAP tool (Beronius et al., J Appl Toxicol, 38:1460-1470, 2018) respectively. Benchmark dose (BMD) modeling was performed using the modeling average mode in BMDS 3.1 and PROAST 66.40, 67 and 69 (human cancer BMDL10; EFSA 2017). For exposure assessment, data from a wide range of sources were evaluated for their reliability. Different target groups (infants/toddlers, children and adults) and exposure scenarios (recreational, sport-active swimmers, top athletes) were considered for oral, inhalation and dermal exposure. Exposure was calculated according to the frequency of swimming events and duration in water. For illustration, cancer risk-related bromate concentrations in pool water were calculated for different target groups, taking into account their exposure using the hBMDL10 and a cancer risk of 1 in 100,000. Convincing evidence was obtained from a multitude of studies that bromate induces oxidative DNA damage and acts as a clastogen in vitro and in vivo. Since statistical modeling of the available genotoxicity data is compatible with both linear as well as non-linear dose-response relationships, bromate should be conservatively considered to be a non-threshold carcinogen. BMD modeling with model averaging for renal cancer studies (Kurokawa et al., J Natl. Cancer Inst, 1983 and 1986a; DeAngelo et al., Toxicol Pathol 26:587-594, 1998) resulted in a median hBMDL10 of 0.65 mg bromate/kg body weight (bw) per day. Evaluation of different age and activity groups revealed that top athletes had the highest exposure, followed by sport-active children, sport-active adults, infants and toddlers, children and adults. The predominant route of exposure was oral (73-98%) by swallowing water, followed by the dermal route (2-27%), while the inhalation route was insignificant (< 0.5%). Accepting the same risk level for all population groups resulted in different guidance values due to the large variation in exposure. For example, for an additional risk of 1 in 100,000, the bromate concentrations would range between 0.011 for top athletes, 0.015 for sport-active children and 2.1 mg/L for adults. In conclusion, the present study shows that health risks due to bromate exposure by swimming pool water cannot be excluded and that large differences in risk exist depending on the individual swimming habits and water concentrations.

[Occurrence of the mycotoxin ochratoxin a in breast milk samples from Germany]. / Zum Vorkommen des Mykotoxins Ochratoxin A in Muttermilchproben aus Deutschland.

INTRODUCTION: Breast milk is the best form of nutrition early in life, yet it may contain contaminants which were ingested by mothers. Ochratoxin A (OTA) is a well-known nephrotoxin with carcinogenic properties and a frequent food contaminant. Ingested OTA is partly excreted with human milk and studies conducted in different countries have shown a wide range of OTA concentrations. The aim of this study was to assess the exposure of infants to OTA by analysing breast milk samples from 2 German areas. METHODS: Breast milk samples were obtained from 90 mothers who had signed an informed consent sheet. The previously validated analytical method (LOD=10 ng/L, LOQ=30 ng/L) involves liquid-liquid extraction and analysis by HPLC with tandem mass spectrometric detection. A preliminary risk assessment was done using the TDI approach. CONCLUSION: More than 50% of the collected 90 milk samples contained detectable OTA levels. Overall, the average concentration in milk from -Dortmund (24.4 ± 21.1 ng/L (n=30), range:<10-100 ng/L) were significant higher than those measured in the Hannover cohort (14.4 ±1 5.1 ng/L (n=60), range: <10-78 ng/L). The OTA levels of 13 samples were measured with concentrations≥ LOQ. The burden of breast milk in different lactation stages, differentiated by colostrum, transitional milk and mature milk, did not differ in the 2 samples collectives Dortmund and Hannover. The infants' exposure was assessed by calculating their OTA intake via human milk. These results were then compared to the recently re-evaluated Tolerable Daily Intake (TDI) of 3 ng/kg body weight/day. In 29% of the cases (with 26 milk samples), the TDI of 3 ng/kg body weight/day was exceeded.In summary, infant exposure to OTA with human milk in Germany is usually low compared to several other countries. Given that in some cases the TDI is exceeded, further efforts to regulate OTA levels in food with the aim of reducing the contamination should be made to minimize the exposure of lactating women to OTA.

Critical evaluation of key evidence on the human health hazards of exposure to bisphenol A.

Despite the fact that more than 5000 safety-related studies have been published on bisphenol A (BPA), there seems to be no resolution of the apparently deadlocked controversy as to whether exposure of the general population to BPA causes adverse effects due to its estrogenicity. Therefore, the Advisory Committee of the German Society of Toxicology reviewed the background and cutting-edge topics of this BPA controversy. The current tolerable daily intake value (TDI) of 0.05 mg/kg body weight [bw]/day, derived by the European Food Safety Authority (EFSA), is mainly based on body weight changes in two- and three-generation studies in mice and rats. Recently, these studies and the derivation of the TDI have been criticized. After having carefully considered all arguments, the Committee had to conclude that the criticism was scientifically not justified; moreover, recently published additional data further support the reliability of the two- and three-generation studies demonstrating a lack of estrogen-dependent effects at and below doses on which the current TDI is based. A frequently discussed topic is whether doses below 5 mg/kg bw/day may cause adverse health effects in laboratory animals. Meanwhile, it has become clear that positive results from some explorative studies have not been confirmed in subsequent studies with higher numbers of animals or a priori defined hypotheses. Particularly relevant are some recent studies with negative outcomes that addressed effects of BPA on the brain, behavior, and the prostate in rodents for extrapolation to the human situation. The Committee came to the conclusion that rodent data can well be used as a basis for human risk evaluation. Currently published conjectures that rats are insensitive to estrogens compared to humans can be refuted. Data from toxicokinetics studies show that the half-life of BPA in adult human subjects is less than 2 hours and BPA is completely recovered in urine as BPA-conjugates. Tissue deconjugation of BPA-glucuronide and -sulfate may occur. Because of the extremely low quantities, it is only of minor relevance for BPA toxicity. Biomonitoring studies have been used to estimate human BPA exposure and show that the daily intake of BPA is far below the TDI for the general population. Further topics addressed in this article include reasons why some studies on BPA are not reproducible; the relevance of oral versus non-oral exposure routes; the degree to which newborns are at higher systemic BPA exposure; increased BPA exposure by infusions in intensive care units; mechanisms of action other than estrogen receptor activation; and the current regulatory status in Europe, as well as in the USA, Canada, Japan, New Zealand, and Australia. Overall, the Committee concluded that the current TDI for BPA is adequately justified and that the available evidence indicates that BPA exposure represents no noteworthy risk to the health of the human population, including newborns and babies.

Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH).

During the last two decades, substantial efforts have been made towards the development and international acceptance of alternative methods to safety studies using laboratory animals. In the EU, challenging timelines for phasing out of many standard tests using laboratory animals were established in the seventh Amending Directive 2003/15/EC to Cosmetics Directive 76/768/EEC. In continuation of this policy, the new European Chemicals Legislation (REACH) favours alternative methods to conventional in vivo testing, if validated and appropriate. Even alternative methods in the status of prevalidation or validation, but without scientific or regulatory acceptance may be used under certain conditions. Considerable progress in the establishment of alternative methods has been made in some fields, in particular with respect to methods predicting local toxic effects and genotoxicity. In more complex important fields of safety and risk assessment such as systemic single and repeated dose toxicity, toxicokinetics, sensitisation, reproductive toxicity and carcinogenicity, it is expected that the development and validation of in silico methods, testing batteries (in vitro and in silico) and tiered testing systems will have to overcome many scientific and regulatory obstacles which makes it extremely difficult to predict the outcome and the time needed. The main reasons are the complexity and limited knowledge of the biological processes involved on one hand and the long time frame until validation and regulatory acceptance of an alternative method on the other. New approaches in safety testing and evaluation using "Integrated Testing Strategies" (ITS) (including combinations of existing data, the use of chemical categories/grouping, in vitro tests and QSAR) that have not been validated or not gained wide acceptance in the scientific community and by regulatory authorities will need a thorough justification of their appropriateness for a given purpose. This requires the availability of knowledge and experience of experts in toxicology. The challenging deadlines for phasing out of in vivo tests in the Cosmetics Amending Directive 2003/15/EC appear unrealistic. Likewise, we expect that the application of validated alternative methods will only have a small or moderate impact on the reduction of in vivo tests under the regimen of REACH, provided that at least the same level of protection of human health as in the past is envisaged. As a consequence, under safety aspects, it appears wise to consider established in vivo tests to be indispensable as basic tools for hazard and risk assessment with respect to systemic single and repeated dose toxicity, sensitisation, carcinogenicity and reproductive toxicity, especially regarding quantitative aspects of risk assessment such as NOAELs, LOAELs and health-related limit values derived from them. Based on the overall evaluation in this review, the authors are of the opinion that in the short- and mid-term, the strategy of the development of alternative methods should be more directed towards the refinement or reduction of in vivo tests. The lessons learnt during these efforts will provide a substantial contribution towards the replacement initiatives in the long-term.

[New drinking water reference values for monocyclic nitro compounds]. / Neue Trinkwasser-Leitwerte für monocyclische Nitroverbindungen.

Nitro compounds are important industrial chemicals with a broad range of applications. During their commercial production or practical use and through leaching from military waste sites they may be released into the environment and thus lead to a contamination of drinking water resources. In the last 15-20 years, the wider public first became aware of nitro compounds as contaminants in groundwater and drinking water resources that originated from manufacturing and processing of secondary explosives during World War II. In 1980, the former Bundesgesundheitsamt (BGA; Federal Health Office) had based its first risk assessment of monocyclic nitro compounds in drinking water on the known carcinogenicity of some aromatic amines in the working environment. On this basis, the BGA recommended for metabolites of aromatic nitro compounds a guide value of 0.1 mug/l for the sum of aromatic amines. From the beginning to the middle of the 1990s, the BGA established a more specific health-related assessment for the individual compounds, but not on the basis of tolerable or acceptable body doses but of dimensionless risk assessment scores ranking their combined toxic and carcinogenic potential on a scale from 1 to 100. In this contribution, we derived new health-based drinking water guide values for 19 nitro(aromatic) compounds and nitramines, including hexogen, octogen, and tetryl as well as the O-nitro compound PETN. All compounds under consideration have been detected within the last 15 years in Germany at contaminated sites close to or directly in groundwater resources for drinking water. For toxicological evaluation and derivation of guideline values for the nitro compounds of interest, the tolerable daily intake (TDI) approach was used for chemicals exhibiting a threshold for toxic effects. This was done by using established tolerable body doses for humans based on an identified NOAEL/LOAEL for the most sensitive toxic endpoint. In the case of non-threshold chemical substances, suitable estimates of excess lifetime cancer risk have been applied.

Toxicological guidelines for monocyclic nitro-, amino- and aminonitroaromatics, nitramines, and nitrate esters in drinking water.

In order to secure a safe drinking water supply, the setting of tolerable/acceptable ceilings of drinking water hygiene is required with regard to xenobiotics resulting from several anthropogenic impacts. This is done in practice by using drinking water guidelines or standards as quantitative objectives. The list of the new EU Directive or the German drinking-water standards is limited to those parameters that have the highest relevance for drinking water quality; nitro compounds (NCs) are not regulated. Because other substances contained in water can also represent a hazard for human health, the German Drinking Water Ordinance clarifies that specific actions must be implemented if compounds other than those regulated appear at concentrations that may be a cause for concern regarding human health. NCs serve as intermediates for dyes, pharmaceuticals, and synthetic materials; they themselves are used as solvents, explosives, and pesticides. During their commercial production or from their use, they may be released to the environment and lead to a contamination of aquatic systems and thus also of drinking water resources. In practice, therefore, a need for assessment is frequently given for relevant NCs. For 19 nitro-, amino-, and aminonitroaromatics, nitramines, and nitrate esters health-based drinking water guide values have been derived. For toxicological evaluation and derivation of guideline values for the NCs of interest, the tolerable daily intake approach was used for chemicals exhibiting a threshold for toxic effects. This was done by using established tolerable body doses for humans based on an identified no-observed-adverse-effect level/low-observed-effect-level for the most sensitive indicator for toxicity. In the case of nonthreshold chemical substances, suitable estimates of excess lifetime cancer risk have been applied.