Relevance of the rat lung tumor response to particle overload for human risk assessment—Update and interpretation of new data since ILSI 2000

The relevance of particle-overload related lung tumors in rats for human risk assessment following chronic inhalation exposures to poorly soluble particulates (PSP) has been a controversial issue for more than three decades. In 1998, an ILSI (International Life Sciences) Working Group of health scientists was convened to address this issue of applicability of experimental study findings of lung neoplasms in rats for lifetime-exposed production workers to PSPs. A full consensus view was not reached by the Workshop participants, although it was generally acknowledged that the findings of lung tumors in rats following chronic inhalation, particle-overload PSP exposures occurred only in rats and no other tested species; and that there was an absence of lung cancers in PSP-exposed production workers. Since the publication of the ILSI Workshop report in 2000, there have been important new data published on the human relevance issue. A thorough and comprehensive review of the health effects literature on poorly soluble particles/lung overload was undertaken and published by an ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals) Task Force in 2013. One of the significant conclusions derived from that technical report was that the rat is unique amongst all species in developing lung tumors under chronic inhalation overload exposures to PSPs. Accordingly, the objective of this review is to provide important insights on the fundamental differences in pulmonary responses between experimentally-exposed rats, other experimental species and occupationally-exposed humans. Briefly, five central factors are described by the following issues. • Interspecies differences in lung responses of rats vs. other rodents, triggering different adverse outcome pathways (AOPs); • Interspecies differences in inhaled particle kinetics in rats vs nonhuman primates and humans triggering differential particle-related pulmonary responses. • Advanced and updated human respiratory tract deposition and retention models allowing more realistic particle translocation/retention estimates. • Differences in morphologies and characterizations of rat vs. human pulmonary tumor types and locations within the respiratory tract. • Comprehensive in-depth analysis of available epidemiological data from PSP production workers that demonstrate no correlation between particle exposures and lung cancers or other non-malignant respiratory diseases. Focusing on these five interrelated/convergent factors clearly demonstrate an inappropriateness in concluding that the findings of lung tumors in rats exposed chronically to high concentrations of PSPs are accurate representations of the risks of lung cancer in PSP-exposed production workers. The most plausible conclusion that can be reached is that results from chronic particle-overload inhalation studies with PSPs in rats have no relevance for determining lung cancer risks in production workers exposed for a working lifetime to these poorly soluble particulate-types

Low-Level Lead Exposure and Intellectual Impairment in Children: Koller et al. Respond

Low-Level Lead Exposure and Intellectual Impairment in Children: Koller et al. Respon

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

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

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

Response to the Reply on behalf of the ‘Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area’ (MAK Commission) by Andrea Hartwig Karlsruhe Institute of Technology (KIT)

Prof. Hartwig commented [1] as chair of the MAK Commission on Morfeld et al. 2015 [2]. We would like to thank the Commission for commenting on our review. However, the MAK Commission did not address a number of important issues raised in our paper

Recent Developments in Low-Level Lead Exposure and Intellectual Impairment in Children

In the last decade children’s blood lead levels have fallen significantly in a number of countries, and current mean levels in developed countries are in the region of 3 μg/dL. Despite this reduction, childhood lead poisoning continues to be a major public health problem for certain at-risk groups of children, and concerns remain over the effects of lead on intellectual development in infants and children. The evidence for lowered cognitive ability in children exposed to lead has come largely from prospective epidemiologic studies. The current World Health Organization/Centers for Disease Control and Prevention blood level of concern reflects this and stands at 10 μg/dL. However, a recent study on a cohort of children whose lifetime peak blood levels were consistently < 10 μg/dL has extended the association of blood lead and intellectual impairment to lower levels of lead exposure and suggests there is no safety margin at existing exposures. Because of the importance of this finding, we reviewed this study in detail along with other recent developments in the field of low-level lead exposure and children’s cognitive development. We conclude that these findings are important scientifically, and efforts should continue to reduce childhood exposure. However, from a public health perspective, exposure to lead should be seen within the many other risk factors impacting on normal childhood development, in particular the influence of the learning environment itself. Current lead exposure accounts for a very small amount of variance in cognitive ability (1–4%), whereas social and parenting factors account for 40% or more

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.International Carbon Black Associatio