Showing papers in "Critical Reviews in Toxicology in 2018"

Non-animal methods to predict skin sensitization (II): an assessment of defined approaches**

Abstract: Skin sensitization is a toxicity endpoint of widespread concern, for which the mechanistic understanding and concurrent necessity for non-animal testing approaches have evolved to a critical juncture, with many available options for predicting sensitization without using animals. Cosmetics Europe and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods collaborated to analyze the performance of multiple non-animal data integration approaches for the skin sensitization safety assessment of cosmetics ingredients. The Cosmetics Europe Skin Tolerance Task Force (STTF) collected and generated data on 128 substances in multiple in vitro and in chemico skin sensitization assays selected based on a systematic assessment by the STTF. These assays, together with certain in silico predictions, are key components of various non-animal testing strategies that have been submitted to the Organization for Economic Cooperation and Development as case studies for skin sensitization. Curated murine local lymph node assay (LLNA) and human skin sensitization data were used to evaluate the performance of six defined approaches, comprising eight non-animal testing strategies, for both hazard and potency characterization. Defined approaches examined included consensus methods, artificial neural networks, support vector machine models, Bayesian networks, and decision trees, most of which were reproduced using open source software tools. Multiple non-animal testing strategies incorporating in vitro, in chemico, and in silico inputs demonstrated equivalent or superior performance to the LLNA when compared to both animal and human data for skin sensitization.

Benchmark dose (BMD) modeling: current practice, issues, and challenges

Abstract: Benchmark dose (BMD) modeling is now the state of the science for determining the point of departure for risk assessment. Key advantages include the fact that the modeling takes account of all of the data for a particular effect from a particular experiment, increased consistency, and better accounting for statistical uncertainties. Despite these strong advantages, disagreements remain as to several specific aspects of the modeling, including differences in the recommendations of the US Environmental Protection Agency (US EPA) and the European Food Safety Authority (EFSA). Differences exist in the choice of the benchmark response (BMR) for continuous data, the use of unrestricted models, and the mathematical models used; these can lead to differences in the final BMDL. It is important to take confidence in the model into account in choosing the BMDL, rather than simply choosing the lowest value. The field is moving in the direction of model averaging, which will avoid many of the challenges of choosing a single best model when the underlying biology does not suggest one, but additional research would be useful into methods of incorporating biological considerations into the weights used in the averaging. Additional research is also needed regarding the interplay between the BMR and the UF to ensure appropriate use for studies supporting a lower BMR than default values, such as for epidemiology data. Addressing these issues will aid in harmonizing methods and moving the field of risk assessment forward.

Non-animal methods to predict skin sensitization (I): the Cosmetics Europe database*

Abstract: Cosmetics Europe, the European Trade Association for the cosmetics and personal care industry, is conducting a multi-phase program to develop regulatory accepted, animal-free testing strategies enabling the cosmetics industry to conduct safety assessments. Based on a systematic evaluation of test methods for skin sensitization, five non-animal test methods (DPRA (Direct Peptide Reactivity Assay), KeratinoSensTM, h-CLAT (human cell line activation test), U-SENSTM, SENS-IS) were selected for inclusion in a comprehensive database of 128 substances. Existing data were compiled and completed with newly generated data, the latter amounting to one-third of all data. The database was complemented with human and local lymph node assay (LLNA) reference data, physicochemical properties and use categories, and thoroughly curated. Focused on the availability of human data, the substance selection resulted nevertheless resulted in a high diversity of chemistries in terms of physico-chemical property ranges and use categories. Predictivities of skin sensitization potential and potency, where applicable, were calculated for the LLNA as compared to human data and for the individual test methods compared to both human and LLNA reference data. In addition, various aspects of applicability of the test methods were analyzed. Due to its high level of curation, comprehensiveness, and completeness, we propose our database as a point of reference for the evaluation and development of testing strategies, as done for example in the associated work of Kleinstreuer et al. We encourage the community to use it to meet the challenge of conducting skin sensitization safety assessment without generating new animal data.

A review of the evidence for endocrine disrupting effects of current-use chemicals on wildlife populations.

Abstract: This review critically examines the data on claimed endocrine-mediated adverse effects of chemicals on wildlife populations. It focuses on the effects of current-use chemicals, and compares their apparent scale and severity with those of legacy chemicals which have been withdrawn from sale or use, although they may still be present in the environment. The review concludes that the effects on wildlife of many legacy chemicals with endocrine activity are generally greater than those caused by current-use chemicals, with the exception of ethinylestradiol and other estrogens found in sewage effluents, which are causing widespread effects on fish populations. It is considered that current chemical testing regimes and risk assessment procedures, at least those to which pesticides and biocides are subjected, are in part responsible for this improvement. This is noteworthy as most ecotoxicological testing for regulatory purposes is currently focused on characterizing apical adverse effect endpoints rather than identifying the mechanism(s) responsible for any observed effects. Furthermore, a suite of internationally standardized ecotoxicity tests sensitive for potential endocrine-mediated effects is now in place, or under development, which should ensure further characterization of substances with these properties so that they can be adequately regulated.

Pyrethroid epidemiology: a quality-based review

Abstract: Pyrethroids are commonly used around the home and in agricultural production to control insects. Human contact to one or more pyrethroid insecticides is likely. Numerous epidemiology studies have evaluated the association between health outcomes in humans and pyrethroid exposure. The purpose of this review was to identify and evaluate the quality of pyrethroid-related epidemiology studies that addressed chronic health effects, and compare findings with animal toxicology studies. We evaluated the quality of 61 studies published between 2000 and 2016 by using elements of outcome, exposure metric, exposure level, and study design. None of the 61 publications demonstrated strong quality for all elements. A few of the outcome measures were strong, particularly those relying upon medical diagnoses. Most of the pyrethroid epidemiology studies used a poor exposure metric, relying upon a single sample of pyrethroid urinary metabolites, which is subject to misclassification of past exposures. In addition, many studies were a cross-sectional design, preventing an evaluation of the temporality of the exposure-disease association. Furthermore, none of the effects observed in the epidemiological literature was concordant with toxicological effects noted in extensive testing of pyrethroids in animals. In order to provide more robust data on potential health outcomes from low dose exposure to pyrethroid insecticides, future epidemiological studies should fully characterize an adverse outcome, include exposure validation components, and quantify exposure over time.

Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution.

Abstract: This article reviews the current legislative requirements for risk assessment of combined exposure to multiple chemicals via multiple exposure routes, focusing on human health and particularly on food-related chemicals. The aim is to identify regulatory needs and current approaches for this type of risk assessment as well as challenges of the implementation of appropriate and harmonized guidance at international level. It provides an overview of the current legal requirements in the European Union (EU), the United States and Canada. Substantial differences were identified in the legal requirements for risk assessment of combined exposure to multiple chemicals and its implementation between EU and non-EU countries and across several regulatory sectors. Frameworks currently proposed and in use for assessing risks from combined exposure to multiple chemicals via multiple routes and different durations of exposure are summarized. In order to avoid significant discrepancies between regulatory sectors or countries, the approach for assessing risks of combined exposure should be based on similar principles for all types of chemicals. OECD and EFSA identified the development of harmonized methodologies for combined exposure to multiple chemicals as a key priority area. The Horizon 2020 project "EuroMix" aims to contribute to the further development of internationally harmonized approaches for such risk assessments by the development of an integrated test strategy using in vitro and in silico tests verified for chemical mixtures based on more appropriate data on potential combined effects. These approaches and testing strategies should be integrated in a scientifically based weight of evidence approach to account for complexity and uncertainty, to improve risk assessment.

The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation.

Abstract: The aryl hydrocarbon receptor (AHR) is not essential to survival, but does act as a key regulator of many normal physiological events. The role of this receptor in toxicological processes has been studied extensively, primarily employing the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, regulation of physiological responses by endogenous AHR ligands remains to be elucidated. Here, we review developments in this field, with a focus on 6-formylindolo[3,2-b]carbazole (FICZ), the endogenous ligand with the highest affinity to the receptor reported to date. The binding of FICZ to different isoforms of the AHR seems to be evolutionarily well conserved and there is a feedback loop that controls AHR activity through metabolic degradation of FICZ via the highly inducible cytochrome P450 1A1. Several investigations provide strong evidence that FICZ plays a critical role in normal physiological processes and can ameliorate immune diseases with remarkable efficiency. Low levels of FICZ are pro-inflammatory, providing resistance to pathogenic bacteria, stimulating the anti-tumor functions, and promoting the differentiation of cancer cells by repressing genes in cancer stem cells. In contrast, at high concentrations FICZ behaves in a manner similar to TCDD, exhibiting toxicity toward fish and bird embryos, immune suppression, and activation of cancer progression. The findings are indicative of a dual role for endogenously activated AHR in barrier tissues, aiding clearance of infections and suppressing immunity to terminate a vicious cycle that might otherwise lead to disease. There is not much support for the AHR ligand-specific immune responses proposed, the differences between FICZ and TCDD in this context appear to be explained by the rapid metabolism of FICZ.

Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future.

Abstract: Thiazolidinedione (TZD) drugs used in the treatment of type 2 diabetes mellitus (T2DM) have proven effective in improving insulin sensitivity, hyperglycemia, and lipid metabolism. Though well tolerated by some patients, their mechanism of action as ligands of peroxisome proliferator-activated receptors (PPARs) results in the activation of several pathways in addition to those responsible for glycemic control and lipid homeostasis. These pathways, which include those related to inflammation, bone formation, and cell proliferation, may lead to adverse health outcomes. As treatment with TZDs has been associated with adverse hepatic, cardiovascular, osteological, and carcinogenic events in some studies, the role of TZDs in the treatment of T2DM continues to be debated. At the same time, new therapeutic roles for TZDs are being investigated, with new forms and isoforms currently in the pre-clinical phase for use in the prevention and treatment of some cancers, inflammatory diseases, and other conditions. The aims of this review are to provide an overview of the mechanism(s) of action of TZDs, a review of their safety for use in the treatment of T2DM, and a perspective on their current and future therapeutic roles.

Modernizing the Bradford Hill criteria for assessing causal relationships in observational data.

Abstract: Perhaps no other topic in risk analysis is more difficult, more controversial, or more important to risk management policy analysts and decision-makers than how to draw valid, correctly qualified causal conclusions from observational data. Statistical methods can readily quantify associations between observed variables using measures such as relative risk (RR) ratios, odds ratios (OR), slope coefficients for exposure or treatment variables in regression models, and quantities derived from these measures. Textbooks of epidemiology explain how to calculate population attributable fractions, attributable risks, burden-of-disease estimates, and probabilities of causation from relative risk (RR) ratios. Despite their suggestive names, these association-based measures have no necessary connection to causation if the associations on which they are based arise from bias, confounding, p-hacking, coincident historical trends, or other noncausal sources. But policy analysts and decision makers need something more: trustworthy predictions - and, later, evaluations - of the changes in outcomes caused by changes in policy variables. This concept of manipulative causation differs from the more familiar concepts of associational and attributive causation most widely used in epidemiology. Drawing on modern literature on causal discovery and inference principles and algorithms for drawing limited but useful causal conclusions from observational data, we propose seven criteria for assessing consistency of data with a manipulative causal exposure-response relationship - mutual information, directed dependence, internal and external consistency, coherent causal explanation of biological plausibility, causal mediation confirmation, and refutation of non-causal explanations - and discuss to what extent it is now possible to automate discovery of manipulative causal dependencies and quantification of causal effects from observational data. We compare our proposed principles for causal discovery and inference to the traditional Bradford Hill considerations from 1965. Understanding how old and new principles are related can clarify and enrich both.

Lead-interacting proteins and their implication in lead poisoning

Abstract: Lead is an important heavy metal used worldwide in several applications, especially in industry. People exposed to lead can develop a wide range of symptoms associated with lead poisoning. Many effects of lead poisoning are reported in the literature, showing a compromising of whole body health, with symptoms related to cardiovascular, immune, bone, reproductive, hematological, renal, gastrointestinal, and nervous system. However, the molecular lead targets as well as the pathways affected by lead poisoning are not completely described. The aim of this study was to construct a map of metabolic pathways impaired in lead poisoning by evaluating which biomolecules are directly affected by lead. Through manual literature curation, we identified proteins which physically interact with lead and subsequently determined the metabolic pathways those proteins are involved with. At total, we identified 23 proteins involved with heme synthesis, calcium metabolism, neurotransmission, among other biological systems, which helps to understand the wide range of lead-poisoning symptoms.

Systematic review of the literature on triclosan and health outcomes in humans

Abstract: The ability of epidemiologic evidence to inform regulatory decisions is largely dependent on the coherence and quality of the published literature. This systematic review examines the quality and consistency of studies assessing health outcomes associated with exposure to triclosan (TCS), an antimicrobial chemical with a short physiologic half-life. We used elements of the Biomonitoring, Environmental Epidemiology, and Short-Lived Chemicals instrument to evaluate aspects of study quality. Each methodological domain - overall design, exposure assessment, and data analysis - was categorized according to three tiers where Tier 1 indicated the highest quality. We also examined consistency of methods, results and reporting as considerations for weight of evidence (WOE) assessment. Studies were considered sufficiently comparable if they addressed the same or similar research questions. Forty-two studies met the criteria for inclusion. Only one randomized cross-over clinical trial of TCS was assigned to Tier 1 for all three domains. Most other studies were assigned to Tier 3 for at least one domain. Although the available literature examined more than 100 different health endpoints and reported hundreds of different measures of association, few studies were considered comparable. For reported measures of association, most were not significantly different from the null; the few statistically significant results represented isolated findings without a discernable across- or within-study pattern. We conclude that the current body of epidemiologic literature does not allow a meaningful WOE assessment due to methodological limitations of individual studies and lack of inter-study consistency. On the other hand, methodologically stronger studies may be used to inform future research.

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

Abstract: 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.

Cobalt and its compounds: update on genotoxic and carcinogenic activities

Abstract: This article summarizes recent experimental and epidemiological data on the genotoxic and carcinogenic activities of cobalt compounds. Emphasis is on the respiratory system, but endogenous exposure from Co-containing alloys used in endoprostheses, and limited data on nanomaterials and oral exposures are also considered. Two groups of cobalt compounds are differentiated on the basis of their mechanisms of toxicity: (1) those essentially involving the solubilization of Co(II) ions, and (2) metallic materials for which both surface corrosion and release of Co(II) ions act in concert. For both groups, identified genotoxic and carcinogenic mechanisms are non-stochastic and thus expected to exhibit a threshold. Cobalt compounds should, therefore, be considered as genotoxic carcinogens with a practical threshold. Accumulating evidence indicates that chronic inhalation of cobalt compounds can induce respiratory tumors locally. No evidence of systemic carcinogenicity upon inhalation, oral or endogenous exposure is available. The scarce data available for Co-based nanosized materials does not allow deriving a specific mode of action or assessment for these species.

Adoption of in vitro systems and zebrafish embryos as alternative models for reducing rodent use in assessments of immunological and oxidative stress responses to nanomaterials.

Abstract: Assessing the safety of engineered nanomaterials (NMs) is paramount to the responsible and sustainable development of nanotechnology, which provides huge societal benefits. Currently, there is no evidence that engineered NMs cause detrimental health effects in humans. However, investigation of NM toxicity using in vivo, in vitro, in chemico, and in silico models has demonstrated that some NMs stimulate oxidative stress and inflammation, which may lead to adverse health effects. Accordingly, investigation of these responses currently dominates NM safety assessments. There is a need to reduce reliance on rodent testing in nanotoxicology for ethical, financial and legislative reasons, and due to evidence that rodent models do not always predict the human response. We advocate that in vitro models and zebrafish embryos should have greater prominence in screening for NM safety, to better align nanotoxicology with the 3Rs principles. Zebrafish are accepted for use by regulatory agencies in chemical safety assessments (e.g. developmental biology) and there is growing acceptance of their use in biomedical research, providing strong foundations for their use in nanotoxicology. We suggest that investigation of the response of phagocytic cells (e.g. neutrophils, macrophages) in vitro should also form a key part of NM safety assessments, due to their prominent role in the first line of defense. The development of a tiered testing strategy for NM hazard assessment that promotes the more widespread adoption of non-rodent, alternative models and focuses on investigation of inflammation and oxidative stress could make nanotoxicology testing more ethical, relevant, and cost and time efficient.

GOLD: human exposure and update on toxic risks.

Abstract: Gold is ubiquitous in the human environment and most people are in contact with it through wearing jewelry, dental devices, implants or therapies for rheumatoid arthritis. Gold is not a nutrient but people are exposed to it as a food colorant and in food chains. The present review discusses the hazards faced in personal and domestic use of gold and the far greater risks presented through occupational exposure to the metal in mining and processing gold ores. In the last situation, regular manual contact or inhalation of toxic or carcinogenic materials like mercury or arsenic, respectively, presents far greater hazard and greatly complicates the evaluation of gold toxicity. The uses and risks presented by new technology and use of nanoparticulate gold in anti-cancer therapies and diagnostic medicine forms a major consideration in gold toxicity, where tissue uptake and distribution are determined largely by particle size and surface characteristics. Many human problems arise through the ability of metallic gold to induce allergic contact hypersensitivity. While gold in jewelry can evoke allergic reactions, other metals such as nickel, chromium and copper present in white gold or alloys exhibit more serious clinical problems. It is concluded that toxic risks associated with gold are low in relation to the vast range of potential routes of exposure to the metal in everyday life.

Understanding outcomes and toxicological aspects of second generation metal-on-metal hip implants: a state-of-the-art review.

Abstract: Hip implants have improved the mobility and quality of life in millions of individuals. This review presents the evolution of scientific knowledge regarding the history and understanding of...

Biological effects of metal degradation in hip arthroplasties

Abstract: Metals and metal alloys are the most used materials in orthopedic implants. The focus is on total hip arthroplasty (THA) that, though well tolerated, may be associated with local and remote adverse effects in the medium-long term. This review aims to summarize data on the biological consequences of the metal implant degradation that have been attributed predominantly to metal-on-metal (MoM) THA. Local responses to metals consist of a broad clinical spectrum ranging from small asymptomatic tissue lesions to severe destruction of bone and soft tissues, which are designated as metallosis, adverse reactions to metal debris (ARMD), aseptic lymphocytic vasculitis associated lesion (ALVAL), and pseudotumors. In addition, the dissemination of metal particles and ions throughout the body has been associated with systemic adverse effects, including organ toxicity, cancerogenesis, teratogenicity, and immunotoxicity. As proved by the multitude of studies in this field, metal degradation may increase safety issues associated with THA, especially with MoM hip systems. Data collection regarding local, systemic and long-term effects plays an essential role to better define any safety risks and to generate scientifically based recommendations.

Computational approaches for skin sensitization prediction

Abstract: Drugs, cosmetics, preservatives, fragrances, pesticides, metals, and other chemicals can cause skin sensitization. The ability to predict the skin sensitization potential and potency of substances is therefore of enormous importance to a host of different industries, to customers' and workers' safety. Animal experiments have been the preferred testing method for most risk assessment and regulatory purposes but considerable efforts to replace them with non-animal models and in silico models are ongoing. This review provides a comprehensive overview of the computational approaches and models that have been developed for skin sensitization prediction over the last 10 years. The scope and limitations of rule-based approaches, read-across, linear and nonlinear (quantitative) structure-activity relationship ((Q)SAR) modeling, hybrid or combined approaches, and models integrating computational methods with experimental results are discussed followed by examples of relevant models. Emphasis is placed on models that are accessible to the scientific community, and on model validation. A dedicated section reports on comparative performance assessments of various approaches and models. The review also provides a concise overview of relevant data sources on skin sensitization.

Shanghai Health Study (2001-2009): What was learned about benzene health effects?

Abstract: The Shanghai Health Study (SHS) was a large epidemiology study conducted as a joint effort between the University of Colorado and Fudan University in Shanghai, China. The study was funded by members of the American Petroleum Institute between 2001 and 2009 and was designed to evaluate the human health effects associated with benzene exposure. Two arms of the SHS included: an occupational-based molecular epidemiology study and several hospital-based case control studies. Consistent with historical literature, following sufficient exposure to relatively high airborne concentrations and years of exposure, the SHS concluded that exposure to benzene resulted in an increased risk of various blood and bone marrow abnormalities such as benzene poisoning, aplastic anemia (AA), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). Non-Hodgkin lymphoma (NHL) was not significantly increased for the exposures examined in this study. Perhaps the most important contribution of the SHS was furthering our understanding of the mechanism of benzene-induced bone marrow toxicity and the importance of identifying the proper subset of MDS relevant to benzene. Investigators found that benzene-exposed workers exhibited bone marrow morphology consistent with an immune-mediated inflammatory response. Contrary to historic reports, no consistent pattern of cytogenetic abnormalities was identified in these workers. Taken together, findings from SHS provided evidence that the mechanism for benzene-induced bone marrow damage was not initiated by chromosome abnormalities. Instead, chronic inflammation, followed by an immune-mediated response, is likely to play a more significant role in benzene-induced disease initiation and progression than previously thought.

Exposure to permethrin and cancer risk: a systematic review.

Abstract: No systematic reviews are available on data from humans on cancer risk from exposure to permethrin, a widely used insecticide for which some animal studies have reported positive findings based on mechanisms that may not be relevant to humans. We identified potentially relevant articles through a search of electronic databases which included all studies of pesticide exposure and human cancer. A total of 18 articles were selected, including six identified from the list of references of other articles. Most articles were based on analyzes of the Agriculture Health Study (AHS); they provided no evidence of an increased risk of cancers of colon, rectum, pancreas, lung, melanoma, female breast, prostate, urinary bladder, as well as non-Hodgkin lymphoma (including its main subtypes), and leukemia. An increased risk of multiple myeloma was reported among AHS members with the highest tertile of estimated permethrin exposure (odds ratio 5.01; 95% confidence interval 2.41-10.42; p for trend <0.01). A subsequent analysis with a larger number of cases found a less pronounced association between permethrin exposure and risk of multiple myeloma; no exposed cases were reported in a separate study. Two case-control studies of childhood leukemia reported an association with biological markers of permethrin metabolites; in another study self-reported exposure to permethrin was associated with risk in children below 1 year of age, but not in older children. In conclusion, permethrin exposure does not seem to entail a risk of cancer in humans. Results on multiple myeloma and childhood leukemia are weak and inconsistent, and require replication in independent populations.

Telomere dynamics and cellular senescence: an emerging field in environmental and occupational toxicology

Abstract: There has been a steady output of epidemiological studies linking environmental and occupational exposures to altered telomere length, showing mainly positive associations with persistent organic pollutants, inverse association with cadmium and inconsistent results with arsenic and lead. A bell-shaped dose-response relationship has been observed for ionizing radiation with telomere shortening at a low dose. Long-term air pollution is associated with telomere shortening, whereas the short-term exposure studies have shown mixed results. There are surprisingly few studies on telomere dynamics in animals. Studies on telomere dynamics and senescence in target tissues of animal strains used in toxicology are warranted. Cell culture studies on ionizing radiation have shown mixed results on telomere length, whereas both telomerase activity and cellular senescence are increased. Studies on persistent organic pollutants indicate telomere shortening, decreased telomerase activity and increased cellular senescence. Cell culture studies on heavy metals and air pollution particles are inconsistent. There is no coherent relationship between exposures, oxidative stress, telomere length, telomerase activity and cellular senescence in experimental studies on environmental or occupational exposures. This may be due to differences in exposure levels (including dose rate), exposure time and models (i.e. cell types and animal strains). Guidelines are needed for best practices on assays for telomere dynamics and cellular senescence in toxicology. However, it deserves notice that experimental studies in cells and animals have revealed important information on the effects of environmental and occupational agents on the maintenance of telomeres and cellular senescence.

Is current risk assessment of non-genotoxic carcinogens protective?

Abstract: Non-genotoxic carcinogens (NGTXCs) do not cause direct DNA damage but induce cancer via other mechanisms. In risk assessment of chemicals and pharmaceuticals, carcinogenic risks are determined using carcinogenicity studies in rodents. With the aim to reduce animal testing, REACH legislation states that carcinogenicity studies are only allowed when specific concerns are present; risk assessment of compounds that are potentially carcinogenic by a non-genotoxic mode of action is usually based on subchronic toxicity studies. Health-based guidance values (HBGVs) of NGTXCs may therefore be based on data from carcinogenicity or subchronic toxicity studies depending on the legal framework that applies. HBGVs are usually derived from No-Observed-Adverse-Effect-Levels (NOAELs). Here, we investigate whether current risk assessment of NGTXCs based on NOAELs is protective against cancer. To answer this question, we estimated Benchmark doses (BMDs) for carcinogenicity data of 44 known NGTXCs. These BMDs were compared to the NOAELs derived from the same carcinogenicity studies, as well as to the NOAELs derived from the associated subchronic studies. The results lead to two main conclusions. First, a NOAEL derived from a subchronic study is similar to a NOAEL based on cancer effects from a carcinogenicity study, supporting the current practice in REACH. Second, both the subchronic and cancer NOAELs are, on average, associated with a cancer risk of around 1% in rodents. This implies that for those chemicals that are potentially carcinogenic in humans, current risk assessment of NGTXCs may not be completely protective against cancer. Our results call for a broader discussion within the scientific community, followed by discussions among risk assessors, policy makers, and other stakeholders as to whether or not the potential cancer risk levels that appear to be associated with currently derived HBGVs of NGXTCs are acceptable.

The development of environmentally acceptable fluorocarbons.

Abstract: Chlorofluorocarbons (CFCs) were introduced in the 1930s as the safe replacements for the toxic and flammable refrigerants being used at that time. Subsequently, hydrochlorofluorocarbons (HC...

Development of an adverse outcome pathway for chemically induced hepatocellular carcinoma: case study of AFB1, a human carcinogen with a mutagenic mode of action.

Abstract: Adverse outcome pathways (AOPs) are frameworks starting with a molecular initiating event (MIE), followed by key events (KEs) linked by KE relationships (KERs), ultimately resulting in a specific adverse outcome. Relevant data for the pathway and each KE/KER are evaluated to assess biological plausibility, weight-of-evidence, and confidence. We aimed to describe an AOP relevant to chemicals directly inducing mutation in cancer critical gene(s), via the formation of chemical-specific pro-mutagenic DNA adduct(s), as an early critical step in tumor etiology. Such chemicals have mutagenic modes-of-action (MOA) for tumor induction. To assist with developing this AOP, Aflatoxin B1 (AFB1) was selected as a case study because it has a rich database and is considered to have a mutagenic MOA. AFB1 information was used to define specific KEs, KERs, and to inform development of a generic AOP for mutagen-induced hepatocellular carcinoma (HCC). In assessing the AFB1 information, it became clear that existing da...

Acute chemical skin injuries in the United States: a review.

Abstract: The objective was to perform a thorough review of published and other available data to elucidate the extent of chemical skin injuries in the US. Chemical skin injuries differ significantly from sk...

Assessing cancer hazards of bitumen emissions - a case study for complex petroleum substances.

Abstract: When assessing cancer hazard and risk associated with a complex petroleum substance, like bitumen emissions, there are often conflicting results related to human, animal and mechanistic studies. Validation of the complex composition to assure that it matches real-world exposures and control of confounders are pivotal factors in study design to allow the necessary read-across during assessments. Several key studies on bitumen emissions in two-year dermal cancer assays reported variable outcomes ranging from high cancer incidence to no cancer incidence. Here, we synthesize findings from published studies to explain the differences and discuss critical factors in cancer hazard evaluation for complex petroleum substances. Using these critical factors, we reviewed relevant human genetic toxicity, mammalian toxicity and mechanistic studies with bitumen to understand the divergence in results. We assess the most reliable and scientifically supported information on the potential carcinogenic hazards of bitumen emissions and comment on quality and completeness of data. Human hazard data are typically considered highest priority because they eliminate the need for interspecies extrapolation and reduce the range of high -to low-dose extrapolation during the risk assessment process. Finally, two well-conducted comprehensive animal studies are discussed that have well-defined test material, exposure concentration and composition representative of worker exposure, evidence of systemic uptake, no confounding exposures and provide consistency across all elements within both studies. Studies that allow effective read-across from human, animal and mechanistic components, control for confounders and are well-validated analytically against workplace exposures, provide the strongest evidence base for evaluating cancer hazard.

A systematic review of epidemiologic studies of styrene and cancer

Abstract: Previous epidemiology reviews of exposure to styrene and the risk of cancer considered studies published through 13 November 2013. Since then, additional relevant research has been published. No review has included meta-analyses. The current systematic review considered research published through June 2017; included meta-analyses of the relationship between any exposure to styrene and cancers identified as being of concern, including non-Hodgkin lymphoma (NHL), leukemia and cancers of the esophagus, pancreas, lung and kidney; and evaluated several other forms of cancer. Meta-relative risks for all studies were 1.14 (95% confidence interval (CI), 0.91-1.43) for NHL, 1.00 (95% CI, 0.80-1.26) for multiple myeloma, 0.98 (95% CI, 0.87-1.09) for all leukemia, 1.03 (95% CI, 0.92-1.15) for esophageal cancer, 1.02 (95% CI, 0.93-1.12) for pancreatic cancer, 1.09 (95% CI, 0.95-1.24) for lung cancer and 1.10 (95% CI, 0.99-1.22) for kidney cancer. Individual studies provided little evidence of exposure-response or induction time trends. Limitations of the available research and of the meta-analyses included reliance in most studies on mortality data rather than on incidence data, lack of quantitative estimates of styrene exposure for individual subjects and lack of information on lifestyle factors. Consideration of all pertinent data, including substantial recent research, indicates that the epidemiologic evidence on the potential carcinogenicity of styrene is inconclusive and does not establish that styrene causes any form of cancer in humans.

Impact of changes in human reproduction on the incidence of endocrine-related diseases.

Abstract: The incidence rates of a wide range of diseases and conditions have increased over the last decades. There is controversy over the origin of these increases, whether they are caused by exposure to compounds thought to have an effect on the endocrine system, the "endocrine disruption theory", or whether some other factor is responsible. In this analysis, the authors take a closer look at the role that changes in reproductive factors have played in this respect. They apply the relative risks of age at first pregnancy and parity or family size to a set of Dutch demographic data from 1955 and 2015 and calculate the percentage of disease increase explained. The decrease in parity over the last decades explains an increase of 26% in testicular cancer. The combination of decrease in parity and increase in maternal age at first pregnancy explains an increase of 34% in hypospadias prevalence. This combination of decreased parity and increased maternal age at pregnancy explains an increase of 24% in childhood obesity prevalence. The authors further point to a perhaps even more profound effect of the trend toward smaller families. This trend has led to an estimated doubling of the proportion of children born from subfertile couples. Since children born from subfertile couples are more likely to be preterm or of low birth weight, the incidence of these conditions must have increased as well. Low birth weight and preterm delivery are risk factors for a wide range of diseases and conditions. The changes in human reproduction over the last decades have had a profound impact on the incidence of a range of diseases and conditions in the next generation and thus provide a sound explanation for a substantial portion of the reported increases. Key messages The incidence rates of a wide range of diseases and conditions have increased in the Western societies over the last decades. Many have argued that these increases are attributable to compounds thought to have effects on the human endocrine system: the endocrine disruption theory This analysis shows, however, that human reproductive factors such as maternal age at first pregnancy and parity explain substantial proportions of the reported increases.

Benzene risk assessment: does new evidence on myelodysplastic syndrome justify a new approach?

Abstract: Epidemiologic findings play an important role in benzene risk assessment, which is utilized to guide the selection of recommended benzene exposure levels to prevent adverse health effects. For decades, excess leukemia risk, especially that in the Pliofilm® cohort, has been the focus of benzene risk assessment. While more stringent benzene standards, often ≤1 ppm, have been promulgated to protect workers from developing leukemia, recent epidemiologic studies have reported elevated risk of myelodysplastic syndrome (MDS). This report aims to examine whether the use of new data on MDS is scientifically warranted in future benzene risk assessments. First, we reviewed current benzene guidelines, regulations, and underlying risk assessments in developed countries. Second, we examined current epidemiologic literature on benzene and MDS, which identified seven studies with simultaneous measures of MDS risk and benzene exposure and 17 studies on MDS in populations potentially exposed to benzene. Next, we ex...

Critical review of renal tubule karyomegaly in non-clinical safety evaluation studies and its significance for human risk assessment.

Abstract: Scientific databases were searched for terms applicable to karyomegaly in renal tubules of laboratory animals used in preclinical safety evaluation studies, and in humans. Renal tubule karyomegaly ...