An intensive study was conducted to provide data on intra- and inter-individual variation in urinary excretion of a series of ingredients in personal care products (parabens, triclosan, ...benzophenones) and bisphenol A (BPA, not expected to be an ingredient) in 8 volunteers over 6 days. Exposure diaries recorded use of personal care products with identified target analytes as ingredients. Participants' usual products were replaced with products without the target analytes for 2 of the 6 days. Urine void volumes and times were recorded. Methyl, ethyl, and n-propylparabens, triclosan, benzophenone-3, and BPA were frequently detected (≥70% of samples). Urinary concentrations of the parabens and triclosan were lower on product replacement days. First morning void concentrations correlated moderately to highly with 24-h composite concentrations for all analytes. Intraclass correlation coefficients (ICCs) for spot samples collected on days with usual product use were low for BPA (0.15), moderate for n-propylparaben and methylparaben (0.39 and 0.56, respectively), and high for ethylparaben, benzophenone-3, and triclosan (0.76, 0.81, and 0.934, respectively); ICCs were consistently higher on the basis of cr-adjusted concentrations. Hydration status adjustment methods were assessed by comparing unadjusted and adjusted concentrations to urinary excretion rates (ER, ng/kg-h) for all analytes and samples. Specific gravity-adjusted concentrations correlated slightly better with ER than creatinine-adjusted concentrations. Within-individual variation in biomarker concentrations was highest for methyl and ethylparabens (2 orders of magnitude variation in spot sample concentrations) and lower for the other analytes (1–1.5 orders of magnitude). This dataset provides insight into the design and interpretation of urinary biomonitoring studies for non-persistent chemicals.
Medicines play an important role in the treatment and prevention of disease. Whereas the side effects on human and animal health resulting directly from treatment have been widely documented, only ...recently have the occurrence and fate of medicines in the environment and the potential consequences for human health been recognized as an issue warranting consideration. Medicines have been shown to be released to soils and to persist in the environment. This study was performed to investigate the potential for a range of veterinary medicines to be taken up from soil by plants used for human consumption and to assess the potential significance of this exposure route in terms of human health. Soil analyses indicated that, for selected substances, measurable residues of these are likely to occur in soils for at least 5 months following application of manure containing these compounds. Experimental studies on the uptake of veterinary medicines into carrot roots (tubers) and lettuce leaves showed that only florfenicol, levamisole, and trimethoprim were taken up by lettuces, whereas diazinon, enrofloxacin, florfenicol, and trimethoprim were detected in carrot roots. Measured concentrations in plant material were used to model potential adult human exposure to these compounds. Although exposure concentrations were appreciable in a few instances, accounting for ∼10% of the acceptable daily intake values (ADI), all were lower than the ADI values, indicating that, at least for compounds with properties similar to those considered here, there is little evidence of an appreciable risk. This exposure route may, however, be important when veterinary medicines have a very low ADI, at which they elicit subtle effects over prolonged periods, or when exposure is occurring via a number of routes at once. Although degradation products (produced in the soil or the plant) were not measured, it is possible for some substances that these could increase the risks to consumers. Keywords: Pharmaceuticals; veterinary; plant uptake; indirect exposure; soil; environment
The toxicokinetic behaviour of nanostructured particles following pulmonary or oral deposition is of great scientific interest. In this toxicokinetic study, following the general principles of OECD ...TG 417, the systemic availability of carbon black, a nanostructured material consisting of agglomerated aggregates was characterised. Each of two grades of beryllium-7 labelled carbon black (MonarchR 1000, oxidized and PrintexR 90; untreated) was administered either intratracheally or orally to adult rats. Independent of route, rats received a single dose of approximately 0.3 mg radiolabelled carbon black. A total of 12 rats were treated per grade and per exposure route: 4 females each for feces/urine/organs and serial blood kinetics; 4 males for organs. At necropsy, the complete suite of organs was analysed for females, but only the lungs, liver, kidney, reproductive organs for males. In the pulmonarily exposed animals, .sup.7Be-MonarchR 1000 and .sup.7Be-PrintexR 90 was detected in feces in the first 3 days after treatment at significant levels, i.e. 17.6% and 8.2%, respectively. In urine, small percentages of 6.7% and 0.4% were observed, respectively. In blood, radioactivity, representative of carbon black was within the background noise of the measurement method. At necropsy, 20 days post-instillation, both test items were practically exclusively found in lungs (75.1% and 91.0%, respectively) and in very small amounts (approximately 0.5%) in the lung-associated lymph nodes (LALN). In the other organs/tissues the test item was not detectable. BAL analyses indicated that carbon black particles were completely engulfed by alveolar macrophages. Radioactivity, representative of carbon black, was not detected beyond the experimentally defined limit of quantitation systemically after deposition in lungs or stomach in rats. Under these experimental conditions, the two CB samples were not shown to translocate beyond the lung or the GI tract into the blood compartment.
Systematic review (SR) is a rigorous, protocol-driven approach designed to minimise error and bias when summarising the body of research evidence relevant to a specific scientific question. Taking as ...a comparator the use of SR in synthesising research in healthcare, we argue that SR methods could also pave the way for a “step change” in the transparency, objectivity and communication of chemical risk assessments (CRA) in Europe and elsewhere. We suggest that current controversies around the safety of certain chemicals are partly due to limitations in current CRA procedures which have contributed to ambiguity about the health risks posed by these substances. We present an overview of how SR methods can be applied to the assessment of risks from chemicals, and indicate how challenges in adapting SR methods from healthcare research to the CRA context might be overcome. Regarding the latter, we report the outcomes from a workshop exploring how to increase uptake of SR methods, attended by experts representing a wide range of fields related to chemical toxicology, risk analysis and SR. Priorities which were identified include: the conduct of CRA-focused prototype SRs; the development of a recognised standard of reporting and conduct for SRs in toxicology and CRA; and establishing a network to facilitate research, communication and training in SR methods. We see this paper as a milestone in the creation of a research climate that fosters communication between experts in CRA and SR and facilitates wider uptake of SR methods into CRA.
This paper sets out to explore the requirements needed to recommend a useable and reliable biomonitoring system for occupational exposure to copper and its inorganic compounds. Whilst workplace ...environmental monitoring of copper is used to measure ambient air concentrations for comparison against occupational exposure limits, biological monitoring could provide complementary information about the internal dose of workers, taking into account intra-individual variability and exposure from all routes. For biomonitoring to be of reliable use for copper, a biomarker and the analytical ability to measure it with sufficient sensitivity must be identified and this is discussed in a range of matrices. In addition, there needs to be a clear understanding of the dose-response relationship of the biomarker with any health-effect (clinical or sub-clinical) or, between the level of external exposure (by any route) and the level of the copper biomarker in the biological matrix being sampled, together with a knowledge of the half-life in the body to determine accurate sampling times. For many biologically non-essential metals the requirements for reliable biomarkers can be met, however, for ‘essential’ metals such as copper that are under homeostatic control, the relationship between exposure (short- or long-term) and the level of any copper biomarker in the blood or urine is complex, which may limit the use and interpretation of measured levels. There are a number of types of biomarker guidance values currently in use which are discussed in this paper, but no values have yet been determined for copper (or its inorganic compounds) due to the complexity of its essential nature; the US The American Conference of Governmental Industrial Hygienists (ACGIH) has however indicated that it is considering the development of a biological exposure index for copper and its compounds. In light of this, we present a review of the reliability of current copper biomarkers and their potential use in the occupational context to evaluate whether there is value in carrying out human biomonitoring for copper exposure. Based on the available evidence we have concluded that the reliable use of biomonitoring of occupational exposure to copper and its application in risk assessment is not possible at the present time.
•Occupational exposure to copper is determined through ambient air monitoring.•Reliable biomonitoring of copper would provide information of internal dose.•Due to homeostasis, reliable biomarkers for copper have not been determined.•Biomarker guidance values have not currently been established for copper.•Biomonitoring of copper and its use in risk assessment is not yet possible.
We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of "granular biopersistent particles ...without known specific toxicity" (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK's human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification.
We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk.
The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species.
Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.
Abstract
In their Commentary Saber et al. (Part Fibre Toxicol 16: 44, 2019) argue that chronic inhalation studies in rats can be used for assessing the lung cancer risk of insoluble nanomaterials. ...The authors make several significant errors in their interpretation and representation of the underlying science. In this Letter to the Editor we discuss these inaccuracies to correct the scientific record. When the science is recounted accurately it does not support Saber et al’s statements and conclusions.
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