Toxicokinetic study following intratracheal instillation or oral gavage of two [7Be]-tagged carbon black samples.

BACKGROUND: 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. METHODS: Each of two grades of beryllium-7 labelled carbon black (Monarch® 1000, oxidized and Printex® 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. RESULTS: In the pulmonarily exposed animals, 7Be-Monarch® 1000 and 7Be-Printex® 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. In orally exposed animals, 98% (7Be-Monarch® 1000) and 99% (7Be-Printex® 90) of the measured radioactivity was detected in feces. Excretion was complete within the first 3 days following treatment. 1.3% and 0.5% of measured activity was attributable to urine in animals that received 7Be-Monarch® 1000 and 7Be-Printex® 90, respectively. Radioactivity was absent in blood and other organs and tissues. CONCLUSION: 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.

Comment on Saber et al. (2019), "Commentary: the chronic inhalation study in rats for assessing lung cancer risk may be better than its reputation".

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.

Evaluating the evidence on genotoxicity and reproductive toxicity of carbon black: a critical review.

Carbon black is produced industrially by the partial combustion or thermal decomposition of gaseous or liquid hydrocarbons under controlled conditions. It is considered a poorly soluble, low toxicity (PSLT) particle. Recently, results from a number of published studies have suggested that carbon black may be directly genotoxic, and that it may also cause reproductive toxicity. Here, we review the evidence from these studies to determine whether carbon black is likely to act as a primary genotoxicant or reproductive toxicant in humans. For the genotoxicity endpoint, the available evidence clearly shows that carbon black does not directly interact with DNA. However, the study results are consistent with the mechanism that, at high enough concentrations, carbon black causes inflammation and oxidative stress in the lung leading to mutations, which is a secondary genotoxic mechanism. For the reproductive toxicity endpoint for carbon black, to date, there are various lung instillation studies and one short-term inhalation study that evaluated a selected number of reproduction endpoints (e.g. gestational and litter parameters) as well as other general endpoints (e.g. gene expression, neurofunction, DNA damage); usually at one time point or using a single dose. It is possible that some of the adverse effects observed in these studies may be the result of non-specific inflammatory effects caused by high exposure doses. An oral gavage study reported no adverse reproductive or developmental effects at the highest dose tested. The overall weight of evidence indicates that carbon black should not be considered a direct genotoxicant or reproductive toxicant.

Silica, silicosis and lung cancer: what level of exposure is acceptable?

Silica, silicosis and lung cancer: what level of exposure is acceptable?

Translational toxicology in setting occupational exposure limits for dusts and hazard classification - a critical evaluation of a recent approach to translate dust overload findings from rats to humans.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Sources of variability in biomarker concentrations.

Human biomonitoring has become a primary tool for chemical exposure characterization in a wide variety of contexts: population monitoring and characterization at a national level, assessment and description of cohort exposures, and individual exposure assessments in the context of epidemiological research into potential adverse health effects of chemical exposures. The accurate use of biomonitoring as an exposure characterization tool requires understanding of factors, apart from external exposure level, that influence variation in biomarker concentrations. This review provides an overview of factors that might influence inter- and intraindividual variation in biomarker concentrations apart from external exposure magnitude. These factors include characteristics of the specific chemical of interest, characteristics of the likely route(s) and frequency of exposure, and physiological characteristics of the biomonitoring matrix (typically, blood or urine). Intraindividual variation in biomarker concentrations may be markedly affected by the relationship between the elimination half-life and the intervals between exposure events, as well as by variation in characteristics of the biomonitored media such as blood lipid content or urinary flow rate. Variation across individuals may occur due to differences in time of sampling relative to exposure events, physiological differences influencing urinary flow or creatinine excretion rates or blood characteristics, and interindividual differences in metabolic rate or other factors influencing the absorption or excretion rate of a compound. Awareness of these factors can assist researchers in improving the design and interpretation of biomonitoring studies.

Biomonitoring for workplace exposure to copper and its compounds is currently not interpretable.

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.

Comment on Balwierz et al. Potential Carcinogens in Makeup Cosmetics. Int. J. Environ. Res. Public Health 2023, 20, 4780.

We read with interest the article by Balwierz et al. [...].

Does carbon black disaggregate in lung fluid? A critical assessment.

Carbon black is an industrially produced particulate form of nearly pure elemental carbon. The basic building blocks of carbon black are (1) primary particles, minute pieces of matter with defined physical boundaries; (2) aggregates, collections of strongly bound or fused particles; and (3) agglomerates, collections of weakly bound aggregates. Industrial carbon black is produced within a closed reactor where the primary particles form aggregates, which become the indivisible entities of carbon black. These aggregates then form agglomerates, which are the typical form of carbon black in commerce. Carbon black is often used in in vitro and in vivo particle toxicology investigations as a reference nanoparticle. The toxicology studies often report the sizes of the primary particles but rarely the sizes of the aggregates or agglomerates. It appears in many cases that there is a limited understanding of the fact that carbon black typically does not exist as primary particles but instead exists as aggregates and agglomerates. Moreover, many toxicology studies manipulate carbon black particles in order to disperse them so that the form of carbon black used in these toxicology studies may be substantially different from the form that may be encountered in the workplace environment. Since the main exposure route for carbon black is inhalation, the question arose as to whether inhaled carbon black may deagglomerate or disaggregate to either smaller aggregates or primary particles when in contact with lung fluids. This question relates to the concern that there may be additional hazards of smaller particles, such as their ability to translocate to tissues and organs beyond the lung and the ability to pass through the blood-brain barrier. The purpose of this assessment is to review the existing literature for evidence as to whether carbon black deagglomerates or disaggregates into smaller aggregates or primary particles when in contact with lung fluid. On the basis of a review of the physical characteristics of commercial carbon black and various toxicology studies, it appears that commercially produced carbon black in contact with lung fluid is unlikely to deagglomerate or disaggregate into smaller aggregates or primary particles.

Potential for effects of land contamination on human health. 2. The case of waste disposal sites.

This review of the epidemiological literature shows that evidence for negative impacts of land contaminated by waste disposal on human health is limited. However, the potential for health impacts cannot be dismissed. The link between residence close to hazardous waste disposal sites and heightened levels of stress and anxiety is relatively well established. However, studies on self-reported outcomes generally suffer from interpretational problems, as subjective symptoms may be due to increased perception and recall. Several recent multiple-site studies support a plausible linkage between residence near waste disposal sites and reproductive effects (including congenital anomalies and low birth weight). There is some conflict in the literature investigating links between land contamination and cancers; the evidence for and against a link is equally balanced and is insufficient to make causal inferences. These are difficult to establish because of lack of data on individual exposures, and other socioeconomic and lifestyle factors that may confound a relationship with area of residence. There is no consistently occurring risk for any specific tumor across multiple studies on sites expected to contain similar contaminants. Further insights on health effects of land contamination are likely to be gained from studies that consider exposure pathways and biomarkers of exposure and effect, similar to those deployed with some success in investigating impacts of cadmium on human health.

Potential for effects of land contamination on human health. 1.The case of cadmium.

A review of the epidemiological literature on the potential effects of land contamination shows that the largest body of contaminant-specific research relates to cadmium (Cd). First, a brief outline of the key issues related to the study of health impact of land contamination is presented. The recent literature is then reviewed for evidence of associations and possible causal relationships between exposure to Cd from land contamination and health impact. A large number of studies focusing on Cd arise because of the ready availability of biomarkers of exposure and effect and the demonstrated link between soil Cd and itai-itai disease (severe renal and bone disorders) via dietary exposure in Japan and China. Where dietary differences yield lower exposures, links have been established between Cd in soil and biomarkers of renal or bone dysfunctions, but not to health impacts per se. Potential effects of Cd exposure were also investigated for other health outcomes, including hypertension, cancer incidence, preterm delivery, and semen parameters. In contrast to renal and bone disorders, results are generally inconsistent and require further lines of evidence. Residence in locations with elevated concentrations of Cd in soil is a poor surrogate for exposure, and there are examples where residents in locations with elevated concentrations of Cd in soil did not appear to suffer serious health consequences.

Framework for the development and application of environmental biological monitoring guidance values.

Human biomonitoring (HBM) is widely recognised as a useful tool to aid assessment of exposure to chemical substances, but our ability to detect hazardous substances (or their metabolites and health effects) often exceeds our understanding of their biological relevance. There are only a few established frameworks for developing and using occupational and environmental biological guidance values (BGVs), mostly for data-rich substances that have been in use for some time. BGVs for new substances and those with unknown dose-response relationships are difficult to derive. An accepted framework based on current scientific knowledge and best practice is therefore urgently needed to help scientists, regulators, and stakeholders to design appropriate HBM studies, interpret HBM data (both for groups and individuals) understand the limitations and to take appropriate action when required. The development and application of such a tool is described here. We derived a conceptual framework that was refined by consultation with an advisory group and workshop. The resulting framework comprised four levels defined by increasing data, with increasing confidence for human health risk assessment. Available data were used for 12 chemicals with expert judgement to illustrate the utility of the framework.

Inhalation toxicity of copper compounds: Results of 14-day range finding study for copper sulphate pentahydrate and dicopper oxide and 28-day subacute inhalation exposure of dicopper oxide in rats.

Inhalation exposure to copper may occur during a range of occupational activities and the purpose of this study was to characterise the toxicological response to repeated inhalation of two copper compounds, representative of copper substances in large-scale production/use. Crl:CD(SD) rats were repeatedly exposed to aerosols of dicopper oxide (Cu2O) or copper sulphate pentahydrate (CuSO4.5 H2O) for 14-days as part of a range finding study at normalised copper doses of 0.18, 0.71, 1.78 and 8.9 mg/m3 Cu. Within a 28-days main study (Cu2O only), animals were repeatedly exposed to 0.2, 0.4, 0.8 and 2.0 mg/m3 Cu2O following OECD TG 412. The main study also consisted of satellite groups exposed for 1-, 2- or 3- weeks as well as a 13-week post-exposure recovery period group. Repeated exposure for 14-days to both copper compounds, normalised for copper content, led to an acute influx of polymorphonuclear leukocytes (neutrophils) and macrophages whilst only CuSO4.5 H2O exposure resulted in epithelial hyperplasia. This differential response may reflect the highly dissolvable nature of CuSO4.5 H2O in lung lining fluid leading to a release of copper ions at the epithelial surface whilst Cu2O is relatively indissolvable at neutral pH. In the 28-day study with Cu2O, an increase in cellularity was also evident in both histological and BALF samples and was dose-related with minimal to mild (neutrophilic) inflammation observed > 0.4 mg/m3 in the lung tissue sections and significant increases from 0.2 mg/m3 in BALF. There were no minimal haematological findings, no clinical findings and systemic organs were unaffected by inhalation exposure to dicopper oxide. The lung cellular response was limited to alveolar histiocytosis and neutrophil influx with no evidence of epithelial hyperplasia or fibrosis and all lung biomarkers returned to control levels within the post-exposure recovery period. Interestingly, the satellite groups showed that this acute cellular response followed a biphasic rather than monotonic pattern with a peak in lung biomarkers between weeks 1-3 and reduction thereafter. This reduction in lung biomarkers occurred during continued exposure and may indicate an adaptive response to copper exposure. Overall, these results show that repeated exposure to copper compounds results in an acute cellular response with no associated pathology and which fully resolved after the cessation of exposure. Therefore, the cellular response is evidence of a controlled and adaptive response associated with the removal of Cu2O from the alveolar surface.

Managing Occupational Exposure to Welding Fume: New Evidence Suggests a More Precautionary Approach is Needed.

Welding is a common industrial process with many millions of workers exposed worldwide. In October 2017, the International Agency for Research on Cancer (IARC) concluded that exposure to welding fumes causes lung cancer in humans, based primarily on the available epidemiological literature. These research studies did not show that the cancer risk differed between mild steel and stainless steel welding but were related to the total welding aerosol. Lung cancer risks were observable at very low exposure levels; below 1 mg m-3 and perhaps as low as 0.1 mg m-3, averaged over a working lifetime. As a result of this IARC evaluation, in Britain, the Health and Safety Executive has acted to strengthen its enforcement expectations for fume control at welding activities. In the light of these developments, it would seem appropriate to review current health-based exposure limits for metal dust and fumes from welding to ensure they are protective.

Carbon Black and Lung Cancer Mortality-A Meta-regression Analysis Based on Three Occupational Cohort Studies.

OBJECTIVES: We review three large cohort studies of occupational exposure to carbon black and association with lung cancer mortality, and conduct a meta-regression to derive an exposure-response relationship. METHODS: Meta-regression analysis of cumulative exposure to carbon black and lung cancer mortality was conducted based on the relative risk estimates reported by three cohort studies of production workers from US, UK, and Germany. RESULTS: A 10 mg/m yr increase in cumulative exposure to carbon black was associated with a relative risk decrease of 1% (relative risk [RR] = 0.99; 95% confidence interval [CI]: 0.87-1.13) for lung cancer mortality. No exposure-response relationship was observed. CONCLUSIONS: This meta-regression analysis of three large occupational mortality studies reports that historic workplace exposures to carbon black were not associated with a significant risk of lung cancer.

Severity scoring of manganese health effects for categorical regression.

Characterizing the U-shaped exposure response relationship for manganese (Mn) is necessary for estimating the risk of adverse health from Mn toxicity due to excess or deficiency. Categorical regression has emerged as a powerful tool for exposure-response analysis because of its ability to synthesize relevant information across multiple studies and species into a single integrated analysis of all relevant data. This paper documents the development of a database on Mn toxicity designed to support the application of categorical regression techniques. Specifically, we describe (i) the conduct of a systematic search of the literature on Mn toxicity to gather data appropriate for dose-response assessment; (ii) the establishment of inclusion/exclusion criteria for data to be included in the categorical regression modeling database; (iii) the development of a categorical severity scoring matrix for Mn health effects to permit the inclusion of diverse health outcomes in a single categorical regression analysis using the severity score as the outcome variable; and (iv) the convening of an international expert panel to both review the severity scoring matrix and assign severity scores to health outcomes observed in studies (including case reports, epidemiological investigations, and in vivo experimental studies) selected for inclusion in the categorical regression database. Exposure information including route, concentration, duration, health endpoint(s), and characteristics of the exposed population was abstracted from included studies and stored in a computerized manganese database (MnDB), providing a comprehensive repository of exposure-response information with the ability to support categorical regression modeling of oral exposure data.

Uptake of veterinary medicines from soils into plants.

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 approximately 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.