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  • The complex puzzle of dietary silver nanoparticles, mucus and microbiota in the gut
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2020-01-10
    Yuqiang Bi; Andrew K. Marcus; Hervé Robert; Rosa Krajmalnik-Brown; Bruce E. Rittmann; Paul Westerhoff; Marie-Hélène Ropers; Muriel Mercier-Bonin

    Hundreds of consumer and commercial products containing silver nanoparticles (AgNPs) are currently used in food, personal-care products, pharmaceutical, and many other applications. Human exposure to AgNPs includes oral intake, inhalation, and dermal contact. The aim of this review was to focus on oral intake, intentional and incidental of AgNPs where well-known antimicrobial characteristics that might affect the microbiome and mucus in the gastrointestinal tract (GIT). This critical review summarizes what is known regarding the impacts of AgNPs on gut homeostasis. It is fundamental to understand the forms of AgNPs and their physicochemical characterization before and during digestion. For example, lab-synthesized AgNPs differ from “real” ingestable AgNPs used as food additives and dietary supplements. Similarly, the gut environment alters the chemical and physical state of Ag that is ingested as AgNPs. Emerging research on in vitro and in vivo rodent and human indicated complex multi-directional relationships among AgNPs, the intestinal microbiota, and the epithelial mucus. It may be necessary to go beyond today’s descriptive approach to a modeling-based ecosystem approach that might quantitatively integrate spatio-temporal interactions among microbial groups, host factors (e.g., mucus), and environmental factors, including lifestyle-based stressors. It is suggested that future research (1) utilize more representative AgNPs, focus on microbe/mucus interactions, (2) assess the effects of environmental stressors for longer and longitudinal conditions, and (3) be integrated using quantitative modeling.

  • Potential adverse health effects of ingested micro- and nanoplastics on humans. Lessons learned from in vivo and in vitro mammalian models
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-12-10
    Laura Rubio, Ricard Marcos, Alba Hernández

    In recent years, increasing global attention has focused on “microplastics” (MPs) and “nanoplastics” (NPs) resulting in many studies on the effects of these compounds on ecological and environmental aspects. These tiny particles (<5000 µm), predominantly derived from the degradation of plastics, pollute the marine and terrestrial ecosystems with the ability to enter into the food chain. In this manner, human consumption of food contaminated with MPs or NPs is unavoidable, but the related consequences remain to be determined. The aim of this review is to complement previous reviews on this topic by providing new studies related to exposure, absorption, and toxicity in mammalian in vivo and in vitro systems. With respect to novel information, gaps and limitations hindering attainment of firm conclusions as well as preparation of a reliable risk assessment are identified. Subsequently, recommendations for in vivo and in vitro testing methods are presented in order to perform further relevant and targeted research studies.

  • Genetic toxicity assessment using liver cell models: past, present, and future
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-11-20
    Xiaoqing Guo, Ji-Eun Seo, Xilin Li, Nan Mei

    Genotoxic compounds may be detoxified to non-genotoxic metabolites while many pro-carcinogens require metabolic activation to exert their genotoxicity in vivo. Standard genotoxicity assays were developed and utilized for risk assessment for over 40 years. Most of these assays are conducted in metabolically incompetent rodent or human cell lines. Deficient in normal metabolism and relying on exogenous metabolic activation systems, the current in vitro genotoxicity assays often have yielded high false positive rates, which trigger unnecessary and costly in vivo studies. Metabolically active cells such as hepatocytes have been recognized as a promising cell model in predicting genotoxicity of carcinogens in vivo. In recent years, significant advances in tissue culture and biological technologies provided new opportunities for using hepatocytes in genetic toxicology. This review encompasses published studies (both in vitro and in vivo) using hepatocytes for genotoxicity assessment. Findings from both standard and newly developed genotoxicity assays are summarized. Various liver cell models used for genotoxicity assessment are described, including the potential application of advanced liver cell models such as 3D spheroids, organoids, and engineered hepatocytes. An integrated strategy, that includes the use of human-based cells with enhanced biological relevance and throughput, and applying the quantitative analysis of data, may provide an approach for future genotoxicity risk assessment.

  • Properties, toxicity and current applications of the biolarvicide spinosad
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-11-11
    Vanessa Santana Vieira Santos, Boscolli Barbosa Pereira

    Characterized as a highly valuable bioactive natural product, spinosad is a pesticide with a complex chemical structure, composed of spinosyn A and D, molecules synthesized by the actinomycete Saccharopolyspora spinosa. The larvicidal activity of spinosad was postulated to be a promising approach to combat crop pests and control species responsible to transmit mosquito-borne illness, including Aedes aegypti. Although initially deemed as relatively safe for non-target organisms and highly effective against insects and crop pests, recent studies focused on the toxicity profile detected the occurrence of side effects in different living species. Thus, the present review was undertaken to describe the properties and characteristics of spinosad. In addition to indicating potential adverse effects on living organisms, alternative uses of the biopesticide as a mixture with different compounds are provided.

  • Key characteristics of 86 agents known to cause cancer in humans
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-10-22
    Daniel Krewski, Michael Bird, Mustafa Al-Zoughool, Nicholas Birkett, Mélissa Billard, Brittany Milton, Jerry M. Rice, Yann Grosse, Vincent J. Cogliano, Mark A. Hill, Robert.A. Baan, Julian Little, Jan M. Zielinski

    Since the inception of the International Agency for Research on Cancer (IARC) in the early 1970s, the IARC Monographs Programme has evaluated more than 1000 agents with respect to carcinogenic hazard; of these, up to and including Volume 119 of the IARC Monographs, 120 agents met the criteria for classification as carcinogenic to humans (Group 1). Volume 100 of the IARC Monographs provided a review and update of Group 1 carcinogens. These agents were divided into six broad categories: (I) pharmaceuticals; (II) biological agents; (III) arsenic, metals, fibers, and dusts; (IV) radiation; (V) personal habits and indoor combustions; and (VI) chemical agents and related occupations. Data on biological mechanisms of action (MOA) were extracted from the Monographs to assemble a database on the basis of ten key characteristics attributed to human carcinogens. After some grouping of similar agents, the characteristic profiles were examined for 86 Group 1 agents for which mechanistic information was available in the IARC Monographs up to and including Volume 106, based upon data derived from human in vivo, human in vitro, animal in vivo, and animal in vitro studies. The most prevalent key characteristic was “is genotoxic”, followed by “alters cell proliferation, cell death, or nutrient supply” and “induces oxidative stress”. Most agents exhibited several of the ten key characteristics, with an average of four characteristics per agent, a finding consistent with the notion that cancer development in humans involves multiple pathways. Information on the key characteristics was often available from multiple sources, with many agents demonstrating concordance between human and animal sources, particularly with respect to genotoxicity. Although a detailed comparison of the characteristics of different types of agents was not attempted here, the overall characteristic profiles for pharmaceutical agents and for chemical agents and related occupations appeared similar. Further in-depth analyses of this rich database of characteristics of human carcinogens are expected to provide additional insights into the MOA of human cancer development.

  • Overview of biological mechanisms of human carcinogens
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-10-20
    Nicholas Birkett, Mustafa Al-Zoughool, Michael Bird, Robert A. Baan, Jan Zielinski, Daniel Krewski

    This review summarizes the carcinogenic mechanisms for 109 Group 1 human carcinogens identified as causes of human cancer through Volume 106 of the IARC Monographs. The International Agency for Research on Cancer (IARC) evaluates human, experimental and mechanistic evidence on agents suspected of inducing cancer in humans, using a well-established weight of evidence approach. The monographs provide detailed mechanistic information about all carcinogens. Carcinogens with closely similar mechanisms of action (e.g. agents emitting alpha particles) were combined into groups for the review. A narrative synopsis of the mechanistic profiles for the 86 carcinogens or carcinogen groups is presented, based primarily on information in the IARC monographs, supplemented with a non-systematic review. Most carcinogens included a genotoxic mechanism.

  • Development of a database on tumors and tumor sites in humans and in experimental animals for 'Group 1 agents identified through volume 109 of the IARC Monographs
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-10-15
    Yann Grosse, Pascale Lajoie, Mélissa Billard, Daniel Krewski, Jerry Rice, Robert A. Baan, Vincent Cogliano, Michael Bird, Jan M. Zielinski

    Volume 100 in the series of IARC Monographs on the Evaluation of Carcinogenic Risks to Humans comprises an update and review of relevant information on all agents determined to induce cancer in humans. These Group 1 agents are categorized in 6 Monographs (Volumes 100A-F) published in 2012. This paper describes the methodology and stringent criteria used in the creation of a comprehensive database on tumors noted in animals and humans for the carcinogens reviewed in Volume 100, and for additional Group 1 agents that were identified in subsequent Monographs through Volume 109. The development of this database involved the systematic collection of relevant data on tumors detected in humans and experimental animals identified by the Working Groups that conducted evaluations reported in the IARC Monographs. The database includes all human tumor sites identified by the Working Groups, along with all tumor sites for which there was sufficient evidence in experimental animals. This database provides a basis for assessing the degree of concordance between tumor sites observed in humans and experimental animals for Group 1 agents identified through Volume 109.

  • Arsenic in edible macroalgae: an integrated approach
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-10-02
    Julieta R. Camurati, Vanesa N. Salomone

    Arsenic is a metalloid naturally present in marine environments. Various toxic elements including arsenic (As) are bioaccumulated by macroalgae. This metalloid is subsequently incorporated as arsenate into the organism due to similarity to phosphate. In recent decades, the use of macroalgae in food has increased as a result of their numerous benefits; however, As consumption may exert potential consequences for human health. The objective of this review was to discuss the articles published up to 2019 on As in seaweed, including key topics such as speciation, toxicity of the most common species in marine macroalgae, and their effects on human health. Further, this review will emphasize the extraction methods and analysis techniques most frequently used in seaweed and the need to develop certified reference materials (CRMs) in order to support the validation of analytical methodologies for As speciation in macroalgae. Finally, this review will discuss current legislation in relation to the risk associated with consumption. The number of articles found and the different approaches, biological, analytical and toxicological, show the growing interest there has been in this field in the last few years. In addition, this review reveals aspects of As chemistry that need further study, such as transformation of organic metalloid species during digestion and cooking, which necessitates analytical improvement and toxicological experiments. Taken together our findings may contribute to revision of current legislation on As content in edible seaweed relating to human health in a growing market.

  • Development of a database on key characteristics of human carcinogens
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-08-04
    Mustafa Al-Zoughool, Michael Bird, Jerry Rice, Robert A. Baan, Mélissa Billard, Nicholas Birkett, Daniel Krewski, Jan M Zielinski

    A database on mechanistic characteristics of human carcinogenic agents was developed by collecting mechanistic information on agents identified as human carcinogens (Group 1) by the International Agency for Research on Cancer (IARC) in the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. A two-phase process is described for the construction of the database according to 24 toxicological endpoints, derived from appropriate test systems that were acquired from data obtained from the mechanisms sections of the IARC Monographs (Section 4) and a supplementary PubMed search. These endpoints were then aligned with 10 key characteristics of human carcinogens that reflect the broader attributes of these agents relating to the development of cancer in humans. The considerations involved in linking of toxicological endpoints to key characteristics are described and specific examples of the determination of key characteristics for six specific agents (tamoxifen, hepatitis B virus, arsenic, ultraviolet and solar radiation, tobacco smoking, and dioxin) are provided. Data for humans and animals were tabulated separately, as were results for in-vivo and for in-vitro sources of information. The database was constructed to support a separate analysis of the expression of these endpoints by 86 Group 1 carcinogens, in-vivo and in-vitro along with an analysis of the key characteristics of these agents.

  • An overview of the current progress, challenges, and prospects of human biomonitoring and exposome studies
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 
    Mariana Zuccherato Bocato, João Paulo Bianchi Ximenez, Christian Hoffmann, Fernando Barbosa

    Human Biomonitoring (HB), the process for determining whether and to what extent chemical substances penetrated our bodies, serves as a useful tool to quantify human exposure to pollutants. In cases of nutrition and physiologic status, HB plays a critical role in the identification of excess or deficiency of essential nutrients. In pollutant HB studies, levels of substances measured in body fluids (blood, urine, and breast milk) or tissues (hair, nails or teeth) aid in the identification of potential health risks or associated adverse effects. However, even as a widespread practice in several countries, most HB studies reflect exposure to a single compound or mixtures which are measured at a single time point in lifecycle. On the other hand, throughout an individual’s lifespan, the contact with different physical, chemical, and social stressors occurs at varying intensities, differing times and durations. Further, the interaction between stressors and body receptors leads to dynamic responses of the entire biological system including proteome, metabolome, transcriptome, and adductome. Bearing this in mind, a relatively new vision in exposure science, defined as the exposome, is postulated to expand the traditional practice of measuring a single exposure to one or few chemicals at one-time point to an approach that addresses measures of exposure to multiple stressors throughout the lifespan. With the exposome concept, the science of exposure advances to an Environment-Wide Association Perspective, which might exhibit a stronger relationship with good health or disease conditions for an individual (phenotype). Thus, this critical review focused on the current progress of HB and exposome investigations, anticipating some challenges, strategies, and future needs to be taken into account for designing future surveys.

  • Paraquat and Parkinson’s disease: a systematic review and meta-analysis of observational studies
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 
    Carolina Vaccari, Regina El Dib, Huda Gomaa, Luciane C Lopes, João Lauro de Camargo

    This investigation aimed to conduct a systematic review of the literature and meta-analysis to determine whether exposure to the herbicide paraquat was associated with the development of Parkinson’s disease (PD). Observational studies that enrolled adults exposed to paraquat with PD as the outcome of interest were searched in the PubMed, Embase, LILACS, TOXNET, and Web of Science databases up to May 2019. Two authors independently selected relevant studies, extracted data, and assessed methodological quality. The evidence certainty was assessed by the GRADE approach, which served as basis for a tentative causality assessment, supplemented by the Bradford Hill criteria when necessary. Results from nine case–control studies indicated that PD occurrence was 25% higher in participants exposed to paraquat. The only cohort investigation included demonstrated a non-significant OR of 1.08. Results from subgroup analyses also indicated higher PD frequency in participants that were exposed to paraquat for longer periods or individuals co-exposed with paraquat and any other dithiocarbamate. Data indicate apositive association between exposure to paraquat and PD occurrence, but the weight-of-evidence does not enable one to assume an indisputable cause–effect relationship between these two conditions. Better designed studies are needed to increase confidence in results.

  • Environmental health effects attributed to toxic and infectious agents following hurricanes, cyclones, flash floods and major hydrometeorological events
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 
    Timothy B. Erickson, Julia Brooks, Eric J. Nilles, Phuong N. Pham, Patrick Vinck

    Extreme hydrometeorological events such as hurricanes and cyclones are increasing in frequency and intensity due to climate change and often associated with flash floods in coastal, urbanized and industrial areas. Preparedness and response measures need to concentrate on toxicological and infectious hazards, the potential impact on environmental health, and threat to human lives. The recognition of the danger of flood water after hurricanes is critical. Effective health management needs to consider the likelihood and specific risks of toxic agents present in waters contaminated by chemical spills, bio-toxins, waste, sewage, and water-borne pathogens. Despite significant progress in the ability to rapidly detect and test water for a wide range of chemicals and pathogens, there has been a lack of implementation to adapt toxicity measurements in the context of flash and hurricane-induced flooding. The aim of this review was to highlight the need to collect and analyze data on toxicity of flood waters to understand the risks and prepare vulnerable communities and first responders. It is proposed that new and routinely used technologies be employed during disaster response to rapidly assess toxicity and infectious disease threats, and subsequently take necessary remedial actions.

  • Evaluation of potential health effects associated with occupational and environmental exposure to styrene – an update
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 
    M.I. Banton, J.S. Bus, J.J. Collins, E. Delzell, H.-P. Gelbke, J.E. Kester, M.M. Moore, R. Waites, S.S. Sarang

    The potential chronic health risks of occupational and environmental exposure to styrene were evaluated to update health hazard and exposure information developed since the Harvard Center for Risk Analysis risk assessment for styrene was performed in 2002. The updated hazard assessment of styrene’s health effects indicates human cancers and ototoxicity remain potential concerns. However, mechanistic research on mouse lung tumors demonstrates these tumors are mouse-specific and of low relevance to human cancer risk. The updated toxicity database supports toxicity reference levels of 20 ppm (equates to 400 mg urinary metabolites mandelic acid + phenylglyoxylic acid/g creatinine) for worker inhalation exposure and 3.7 ppm and 2.5 mg/kg bw/day, respectively, for general population inhalation and oral exposure. No cancer risk value estimates are proposed given the established lack of relevance of mouse lung tumors and inconsistent epidemiology evidence. The updated exposure assessment supports inhalation and ingestion routes as important. The updated risk assessment found estimated risks within acceptable ranges for all age groups of the general population and workers with occupational exposures in non-fiber-reinforced polymer composites industries and fiber-reinforced polymer composites (FRP) workers using closed-mold operations or open-mold operations with respiratory protection. Only FRP workers using open-mold operations not using respiratory protection have risk exceedances for styrene and should be considered for risk management measures. In addition, given the reported interaction of styrene exposure with noise, noise reduction to sustain levels below 85 dB(A) needs be in place.

  • Risk assessment of lithium-ion battery explosion: chemical leakages
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-04-12
    Yoo Jung Park, Min Kook Kim, Hyung Sik Kim, Byung Mu Lee

    Use of lithium-ion batteries has raised safety issues owing to chemical leakages, overcharging, external heating, or explosions. A risk assessment was conducted for hydrofluoric acid (HF) and lithium hydroxide (LiOH) which potential might leak from lithium-ion batteries. The inhalation no-observed-adverse-effect-level (NOAEL) for HF was 0.75 mg/kg/d. When a lithium-ion battery explodes in a limited space, HF emissions amount to 10–100 ppm. Assuming the worst-case scenario, the conversion rate was calculated to be 81.8 mg/m3, and the average daily dose (ADD) was 19.5 mg/kg/d. Consequently, the margin of exposure (MOE = NOAEL/ADD) was 0.034, a value which constitutes an unsafe inhalation exposure for HF. Conversely, skin toxicity NOAEL for LiOH was 41.35 mg/kg/d−. This LiOH value reflects the amount of lithium in the lithium-ion battery, which is generated upon contact between water and the electrolyte. The quantity of lithium in a mobile phone is approximately 295 mg, and systemic exposure dose (SED) was 4.92 mg/kg/d. Accordingly, the MOE (NOAEL/SED) value was 8.41, and skin exposure of LiOH was deemed as safe for humans. However, it is important that Energy Storage System batteries still require safety measures and technologies for next-generation batteries, to prevent any potential explosions of lithium-ion batteries.

  • The cationic (calcium and lead) and enzyme conundrum
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-03-27
    Jane Kasten-Jolly, David A. Lawrence

    The environmental toxicant lead (Pb) and the essential element calcium (Ca) play an interactive role in extracellular and intracellular regulatory functions that affect health. Lead’s usurping calcium binding sites, as well as its interactions with thiols and phosphates have been suggested to be the basis for adverse effects on many organ systems especially the nervous system. Among regulatory processes controlled by Ca are calmodulin-dependent phosphodiesterase, calmodulin-dependent protein kinases, calmodulin inhibitor sensitive potassium channels, and calmodulin-independent protein kinase C (PKC) activation. This review focused on Pb studies describing the modulation of PKC, which is also regulated by steroids. Steroid hormone regulation may relate to a focal point for the sex differences of Pb and cellular signaling events. Picomolar concentrations of Pb may stimulate partially purified PKC, but higher concentrations inhibit activity. Although knowledge exists regarding Pb and PKC isoforms, especially interaction of Pb with the purified enzyme, there are conflicting reports concerning metal-mediated activation or inhibition of PKC and downstream signaling events. The effect of Pb on PKC in vivo remains elusive. Most reports of Pb and PKC in whole animal and human studies indicated that Pb either inhibits PKC or exerts no significant effect. However, most of the animal studies were performed with males. Recent studies performed with females and males separately revealed that females and males respond to Pb quite differently, and for this reason, it is suggested that future Pb studies of PKC and other biomedical investigations be performed with females and males.

  • Hearing loss, lead (Pb) exposure, and noise: a sound approach to ototoxicity exploration
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-01-21
    Krystin Carlson, Richard L. Neitzel

    To determine the state of the research on ototoxic properties of Pb, evaluate possible synergistic effects with concurrent noise exposure, and identify opportunities to improve future research, we performed a review of the peer-reviewed literature to identify studies examining auditory damage due to Pb over the past 50 years. Thirty-eight studies (14 animal and 24 human) were reviewed. Of these, 24 suggested potential ototoxicity due to Pb exposure, while 14 found no evidence of ototoxicity. More animal studies are needed, especially those investigating Pb exposure levels that are occupationally and environmentally relevant to humans. Further investigations into potential interactions of Pb in the auditory system with other hazards and compounds that elicit ototoxicity are also needed in animal models. To better assess the effects of Pb exposure on the human auditory system and the possibility of a synergism with noise, future epidemiological studies need to carefully consider and address four main areas of uncertainty: (1) hearing examination and quantification of hearing loss, (2) Pb exposure evaluation, (3) noise exposure evaluation, and (4) the personal characteristics of those exposed. Two potentially confounding factors, protective factors and mixtures of ototoxicants, also warrant further exploration.

  • Toxicity and applications of surfactin for health and environmental biotechnology
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2019-01-07
    Vanessa Santana Vieira Santos, Edgar Silveira, Boscolli Barbosa Pereira

    Characterized as one of the most potent biosurfactants, surfactin is a cyclic lipopeptide synthesized by several strains of Bacillus genus. The aim of this review was to present the physicochemical and structural properties of surfactin and to demonstrate advances and applications of this biosurfactant for health and environmental biotechnology. Further, this review also focused on toxicological effects of surfactin on in vivo and in in vitro systems. The hydrophobic nature of surfactin enables interaction with membrane-bound phospholipids and indicates the ability of the molecule to act as a new weapon with respect to therapeutic and environmental properties. Seeking to avoid environmental contamination produced by widespread use of synthetic surfactants, surfactin emerges as a biological control agent against pathogen species owing to its antibacterial and antiviral properties. In addition, the mosquitocidal activity of surfactin was suggested as new strategy to control disease vectors. The current findings warrant future research to assess the toxicity of surfactin to enable an optimizing anticancer therapy and to seek refined methodologies, including nanotechnology techniques, to allow for an improved delivery of the biogenic molecule on target cells.

  • Health effects associated with occupational exposure to hand-arm or whole body vibration
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-12-25
    Kristine Krajnak

    Workers in a number of different occupational sectors are exposed to workplace vibration on a daily basis. This exposure may arise through the use of powered-hand tools or hand-transmitted vibration (HTV). Workers might also be exposed to whole body vibration (WBV) by driving delivery vehicles, earth moving equipment, or through use of tools that generate vibration at low dominant frequencies and high amplitudes, such as jackhammers. Occupational exposure to vibration has been associated with an increased risk of musculoskeletal pain in the back, neck, hands, shoulders, and hips. Occupational exposure may also contribute to the development of peripheral and cardiovascular disorders and gastrointestinal problems. In addition, there are more recent data suggesting that occupational exposure to vibration may enhance the risk of developing certain cancers. The aim of this review is to provide an assessment of the occupations where exposure to vibration is most prevalent, and a description of the adverse health effects associated with occupational exposure to vibration. This review will examine (1) various experimental methods used to measure and describe the characteristics of vibration generated by various tools and vehicles, (2) the etiology of vibration-induced disorders, and (3) how these data were employed to assess and improve intervention strategies and equipment that reduces the transmission of vibration to the body. Finally, there is a discussion of the research gaps that need to be investigated to further reduction in the incidence of vibration-induced illnesses and injuries.

  • Environmental contaminants and preeclampsia: a systematic literature review
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-12-24
    Emma M. Rosen, MG Isabel Muñoz, Thomas McElrath, David E. Cantonwine, Kelly K. Ferguson

    Preeclampsia is a medical condition specific to pregnancy characterized by high blood pressure and protein in the woman’s urine, indicating kidney damage. It is one of the most serious reproductive conditions, posing substantial risks to the baby and potentially fatal for the mother. The causes of preeclampsia are largely unknown and environmental contaminants merit further investigation. The aim of this review was to determine the association between environmental chemical exposures and preeclampsia. PubMed was searched for articles examining a priori chemical exposures and preeclampsia through April 2018. Studies were included in our review if they included at least 10 cases, evaluated preeclampsia independent of gestational hypertension, and used either measured or modeled exposure assessments. Our review contained 28 investigations examining persistent organic pollutants (POP) (6 studies), drinking water contaminants (1 study), atmospheric pollutants (11 studies), metals and metalloids (6 studies), and other environmental contaminants (4 studies). There were an insufficient number of investigations on most chemicals to draw definitive conclusions, but strong evidence existed for an association between preeclampsia and cadmium (Cd). There is suggestive evidence for associations between nitrogen dioxide (NO2), particulate matter (PM)2.5, and traffic exposure with preeclampsia. There is evidence for an association between preeclampsia and Cd but insufficient literature to evaluate many other environmental chemicals. Additional studies using repeated measures, appropriate biological matrices, and mixtures methods are needed to expand this area of research and address the limitations of previous studies.

  • Importance of bacterial biodegradation and detoxification processes of microcystins for environmental health
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-10-29
    Isaac Yaw Massey, Xian Zhang, Fei Yang

    Microcystins (MC) the most frequently reported cyanobacterial harmful algal bloom toxins primarily found in some species of freshwater genera pose a serious threat to human and animal health. To reduce health risks associated with MC exposure it is important to remove these toxins found in drinking and recreational waterbodies. Since the physical and chemical water treatment methods are inefficient in completely degrading MC, alternative approaches to effectively detoxify MC have become the focus of global research. The aim of this review was to provide the current approach to cost-effective biological treatment methods which utilize bacteria to degrade MC without generation of harmful by-products. In addition, the catabolic pathways involved in MC-degradation involving proteins encoded mlr gene cluster, intermediate products and efficiencies of bacteria strain/bacteria community are presented and compared.

  • Polybrominated diphenyl ether (PBDE) neurotoxicity: a systematic review and meta-analysis of animal evidence
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-10-23
    David C. Dorman, Weihsueh Chiu, Barbara F. Hales, Russ Hauser, Kamin J. Johnson, Ellen Mantus, Susan Martel, Karen A. Robinson, Andrew A. Rooney, Ruthann Rudel, Sheela Sathyanarayana, Susan L. Schantz, Katrina M. Waters

    A recent systematic review (SR) and meta-analysis of human studies found an association between prenatal serum polybrominated diphenyl ethers (PBDE) concentrations and a decrease in the IQ of children. A SR of experimental developmental animal PBDE-mediated neurotoxicity studies was performed in the present study. Outcomes assessed included measures related to learning, memory, and attention, which parallel the intelligence-related outcomes evaluated in the human studies SR. PubMed, Embase, and Toxline were searched for relevant experimental non-human mammalian studies. Evaluation of risk of bias (RoB) and overall body of evidence followed guidance developed by the National Toxicology Program. Animal studies using varying designs and outcomes were available for BDEs 47, 99, 153, 203, 206, and 209 and the technical mixture DE-71. Study reporting of methods and results was often incomplete leading to concerns regarding RoB. A meta-analysis of 6 Morris water maze studies showed evidence of a significant increase in last trial latency (effect size of 25.8 [CI, 20.3 to 31.2]) in PBDE-exposed animals with low heterogeneity. For most endpoints, there were unexplained inconsistencies across studies and no consistent evidence of a dose-response relationship. There is a “moderate” level of evidence that exposure to BDEs 47, 99, and 209 affects learning. For other PBDEs and other endpoints, the level of evidence was “low” or “very low”. The meta-analysis led to stronger conclusions than that based upon a qualitative review of the evidence. The SR also identified RoB concerns that might be remedied by better study reporting.

  • Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-09-10
    David C. Dorman, Weihsueh Chiu, Barbara F. Hales, Russ Hauser, Kamin J. Johnson, Ellen Mantus, Susan Martel, Karen A. Robinson, Andrew A. Rooney, Ruthann Rudel, Sheela Sathyanarayana, Susan L. Schantz, Katrina M. Waters

    Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract malformations. The aim of this investigation was to conduct systematic reviews of human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. PubMed, Embase, and Toxline were searched for relevant human and experimental animal studies on August 15, 2016. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for quality and data extracted for analysis. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. The search yielded 6 relevant human studies and 19 animal studies. Meta-analysis of 5 human observational prospective cohort studies showed that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in boys (−4.07 [CI, −6.49 to −1.66] % decrease per log10 rise in DEHP metabolites). Meta-analysis and meta-regression of the 19 experimental animal studies found reduced AGD with DEHP treatment, with a dose-response gradient, and with heterogeneity explained by species and strain. There is a moderate level of evidence from human investigations and a high level of data from animal studies that in utero exposure to DEHP decreases AGD. Based upon the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans on the basis of effects on AGD.

  • Attention Restoration Theory II: a systematic review to clarify attention processes affected by exposure to natural environments
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-08-21
    Matt P. Stevenson, Theresa Schilhab, Peter Bentsen

    Attention Restoration Theory (ART) predicts exposure to natural environments may lead to improved cognitive performance through restoration of a limited cognitive resource, directed attention. A recent review by Ohly and colleagues (2016) uncovered substantial ambiguity surrounding details of directed attention and how cognitive restoration was tested. Therefore, an updated systematic review was conducted to identify relevant cognitive domains from which to describe elements of directed attention sensitive to the restoration effect. Forty-two articles that tested natural environments or stimuli against a suitable control, and included an objective measure of cognitive performance, had been published since July 2013. Articles were subjected to screening procedures and quality appraisal. Random effects meta-analyses were performed to calculate pooled effect sizes across 8 cognitive domains using data from 49 individual outcome measures. Results showed that working memory, cognitive flexibility, and to a less-reliable degree, attentional control, are improved after exposure to natural environments, with low to moderate effect sizes. Moderator analyses revealed that actual exposures to real environments may enhance the restoration effect within these three domains, relative to virtual exposures; however, this may also be due to differences in the typical lengths of exposure. The effect of a participants’ restoration potential, based upon diagnosis or fatigue-induction, was less clear. A new framework is presented to qualify the involvement of directed attention-related processes, using examples of tasks from the three cognitive domains found to be sensitive to the restoration effect. The review clarifies the description of cognitive processes sensitive to natural environments, using current evidence, while exploring aspects of protocol that appear influential to the strength of the restoration effect.

  • Application of prioritization approaches to optimize environmental monitoring and testing of pharmaceuticals
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-05-01
    Emily E. Burns, Laura J. Carter, Jason Snape, Jane Thomas-Oates, Alistair B.A. Boxall

    Pharmaceuticals are ubiquitous in the natural environment with concentrations expected to rise as human population increases. Environmental risk assessments are available for a small portion of pharmaceuticals in use, raising concerns over the potential risks posed by other drugs that have little or no data. With >1900 active pharmaceutical ingredients in use, it would be a major task to test all of the compounds with little or no data. Desk-based prioritization studies provide a potential solution by identifying those substances that are likely to pose the greatest risk to the environment and which, therefore, need to be considered a priority for further study. The aim of this review was to (1) provide an overview of different prioritization exercises performed for pharmaceuticals in the environment and the results obtained; and (2) propose a new holistic risk-based prioritization framework for drugs in the environment. The suggested models to underpin this framework are discussed in terms of validity and applicability. The availability of data required to run the models was assessed and data gaps identified. The implementation of this framework may harmonize pharmaceutical prioritization efforts and ensure that, in the future, experimental resources are focused on molecules, endpoints, and environmental compartments that are biologically relevant.

  • Extracellular vesicles released in response to respiratory exposures: implications for chronic disease
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-05-01
    Birke J. Benedikter, Emiel F. M. Wouters, Paul H. M. Savelkoul, Gernot G. U. Rohde, Frank R. M. Stassen

    Extracellular vesicles (EV) are secreted signaling entities that enhance various pathological processes when released in response to cellular stresses. Respiratory exposures such as cigarette smoke and air pollution exert cellular stresses and are associated with an increased risk of several chronic diseases. The aim of this review was to examine the evidence that modifications in EV contribute to respiratory exposure-associated diseases. Publications were searched using PubMed and Google Scholar with the search terms (cigarette smoke OR tobacco smoke OR air pollution OR particulate matter) AND (extracellular vesicles OR exosomes OR microvesicles OR microparticles OR ectosomes). All original research articles were included and reviewed. Fifty articles were identified, most of which investigated the effect of respiratory exposures on EV release in vitro (25) and/or on circulating EV in human plasma (24). The majority of studies based their main observations on the relatively insensitive scatter-based flow cytometry of EV (29). EV induced by respiratory exposures were found to modulate inflammation (19), thrombosis (13), endothelial dysfunction (11), tissue remodeling (6), and angiogenesis (3). By influencing these processes, EV may play a key role in the development of cardiovascular diseases and chronic obstructive pulmonary disease and possibly lung cancer and allergic asthma. The current findings warrant additional research with improved methodologies to evaluate the contribution of respiratory exposure-induced EV to disease etiology, as well as their potential as biomarkers of exposure or risk and as novel targets for preventive or therapeutic strategies.

  • Human biomarker interpretation: the importance of intra-class correlation coefficients (ICC) and their calculations based on mixed models, ANOVA, and variance estimates
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-08-01
    Joachim D. Pleil, M. Ariel Geer Wallace, Matthew A. Stiegel, William E. Funk

    Human biomonitoring is the foundation of environmental toxicology, community public health evaluation, preclinical health effects assessments, pharmacological drug development and testing, and medical diagnostics. Within this framework, the intra-class correlation coefficient (ICC) serves as an important tool for gaining insight into human variability and responses and for developing risk-based assessments in the face of sparse or highly complex measurement data. The analytical procedures that provide data for clinical and public health efforts are continually evolving to expand our knowledge base of the many thousands of environmental and biomarker chemicals that define human systems biology. These chemicals range from the smallest molecules from energy metabolism (i.e., the metabolome), through larger molecules including enzymes, proteins, RNA, DNA, and adducts. In additiona, the human body contains exogenous environmental chemicals and contributions from the microbiome from gastrointestinal, pulmonary, urogenital, naso-pharyngeal, and skin sources. This complex mixture of biomarker chemicals from environmental, human, and microbiotic sources comprise the human exposome and generally accessed through sampling of blood, breath, and urine. One of the most difficult problems in biomarker assessment is assigning probative value to any given set of measurements as there are generally insufficient data to distinguish among sources of chemicals such as environmental, microbiotic, or human metabolism and also deciding which measurements are remarkable from those that are within normal human variability. The implementation of longitudinal (repeat) measurement strategies has provided new statistical approaches for interpreting such complexities, and use of descriptive statistics based upon intra-class correlation coefficients (ICC) has become a powerful tool in these efforts. This review has two parts; the first focuses on the history of repeat measures of human biomarkers starting with occupational toxicology of the early 1950s through modern applications in interpretation of the human exposome and metabolic adverse outcome pathways (AOPs). The second part reviews different methods for calculating the ICC and explores the strategies and applications in light of different data structures.

  • The obesogen tributyltin induces features of polycystic ovary syndrome (PCOS): a review
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-07-17
    Eduardo Merlo, Ian V. Silva, Rodolfo C. Cardoso, Jones B. Graceli

    Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome characterized by abnormal reproductive cycles, irregular ovulation, and hyperandrogenism. This complex disorder has its origins both within and outside the hypothalamic-pituitary-ovarian axis. Cardio-metabolic factors, such as obesity and insulin resistance, contribute to the manifestation of the PCOS phenotype. Polycystic ovary syndrome is one of the most common endocrine disorders among women of reproductive age. Growing evidence suggested an association between reproductive and metabolic features of PCOS and exposure to endocrine-disrupting chemicals (EDC), such as bisphenol A. Further, the environmental obesogen tributyltin (TBT) was shown to induce reproductive, metabolic and cardiovascular abnormalities resembling those found in women and animal models of PCOS. However, the causal link between TBT exposure and PCOS development remains unclear. The objective of this review was to summarize the most recent research findings on the potential association between TBT exposure and development of PCOS-like features in animal models and humans.

  • Risk management of free radicals involved in air travel syndromes by antioxidants
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-01-17
    Jeum-Nam Kim, Byung-Mu Lee

    Frequent air travelers and airplane pilots may develop various types of illnesses. The environmental risk factors associated with air travel syndromes (ATS) or air travel–related adverse health outcomes raised concerns and need to be assessed in the context of risk management and public health. Accordingly, the aim of the present review was to determine ATS, risk factors, and mechanisms underlying ATS using scientific data and information obtained from Medline, Toxline, and regulatory agencies. Additional information was also extracted from websites of organizations, such as the International Air Transport Association (IATA), International Association for Medical Assistance to Travelers (IAMAT), and International Civil Aviation Organization (ICAO). Air travelers are known to be exposed to environmental risk factors, including circadian rhythm disruption, poor cabin air quality, mental stress, high altitude conditions, hormonal dysregulation, physical inactivity, fatigue, biological infections, and alcoholic beverage consumption. Consequences of ATS attributed to air travel include sleep disturbances (e.g., insomnia), mental/physical stress, gastrointestinal disorders, respiratory diseases, circulatory-related dysfunction, such as cardiac arrest and thrombosis and, at worst, mechanical and terrorism-related airplane crashes. Thus safety measures in the cabin before or after takeoff are undertaken to prevent illnesses or accidents related to flight. In addition, airport quarantine systems are strongly recommended to prepare for any ultimate adverse circumstances. Routine monitoring of environmental risk factors also needs to be considered. Frequently, the mechanisms underlying these adverse manifestations involve free radical generation. Therefore, antioxidant supplementation may help to reduce or prevent adverse outcomes by mitigating health risk factors associated with free radical generation.

  • Arsenic, cadmium, and mercury-induced hypertension: mechanisms and epidemiological findings
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-02-15
    Airton da Cunha Martins Jr, Maria Fernanda Hornos Carneiro, Denise Grotto, Joseph A Adeyemi, Fernando Barbosa Jr.

    Arsenic (As), cadmium (Cd), and mercury (Hg) are toxic elements widely distributed in the environment. Exposure to these elements was attributed to produce several acute and chronic illnesses including hypertension. The aim of this review is to provide a summary of the most frequently proposed mechanisms underlying hypertension associated with As, Cd, and Hg exposure including: oxidative stress, impaired nitric oxide (NO) signaling, modified vascular response to neurotransmitters and disturbed vascular muscle Ca2+ signaling, renal damage, and interference with the renin–angiotensin system. Due to the complexity of the vascular system, a combination rather than a singular mechanism needs to be considered. In addition, epidemiological findings showing the relationship between various biomarkers of metal exposure and hypertension are described. Given the complex etiology of hypertension, further epidemiological studies evaluating the roles of confounding factors such as age, gender, and life style are still necessary.

  • In vivo and in vitro methods for evaluating soil arsenic bioavailability: relevant to human health risk assessment
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-03-19
    Karen D Bradham, Gary L Diamond, Michele Burgess, Albert Juhasz, Julie M Klotzbach, Mark Maddaloni, Clay Nelson, Kirk Scheckel, Sophia M Serda, Marc Stifelman, David J Thomas

    Arsenic (As) is the most frequently occurring contaminant on the priority list of hazardous substances, which lists substances of greatest public health concern to people living at or near U.S. National Priorities List site. Accurate assessment of human health risks from exposure to As-contaminated soils depends on estimating its bioavailability, defined as the fraction of ingested As absorbed across the gastrointestinal barrier and available for systemic distribution and metabolism. Arsenic bioavailability varies among soils and is influenced by site-specific soil physical and chemical characteristics and internal biological factors. This review describes the state-of-the science that supports our understanding of oral bioavailability of soil As, the methods that are currently being explored for estimating soil As relative bioavailability (RBA), and future research areas that could improve our prediction of the oral RBA of soil As in humans. The following topics are addressed: (1) As soil geochemistry; (2) As toxicology; (3) in vivo models for estimating As RBA; (4) in vitro bioaccessibility methods; and (5) conclusions and research needs.

  • Letter to the editor “The resilience of the beehive”
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-01-08
    Henk A. Tennekes

    A recent quantitative weight of evidence (QWoE) assessment of higher tier studies on the toxicity and risks of neonicotinoids in honeybees by Solomon and Stephenson reported a colony-level no-observed-adverse effect concentration (NOAEC) of 25 µg/kg (ppb) for imidacloprid and clothianidin. The toxicity of these insecticides to honeybees is however known to be reinforced with chronic exposure, and extrapolation of time-to lethal-effect toxicity plots compiled from published studies indicate that an imidacloprid level of 0.25 ppb, i.e. one-hundredth of the reported colony NOAEC, would kill a large proportion of bees nearing the end of their life. This huge discrepancy points to the impressive resilience of beehives in counteracting lethal effects of neonicotinoids, as long as the colony remains otherwise healthy with a productive queen that is able to maintain the colony population. The explicit connection between innate immunity loss and the neonicotinoids leading to infestation with a wide variety of pathogens appears to be the decisive factor that ultimately bring down stressed colonies.

  • Response to Tennekes (2018) “The Resilience of the Beehive” Journal of Toxicology and Environmental Health B 20: 316–386
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2018-01-09
    Keith R Solomon, Gladys L Stephenson

    This paper is a response to a letter from Dr. H Tennekes (“The Resilience of the Beehive” Journal of Toxicology and Environmental Health B 20: 316–386). Here we emphasize that our quantitative weight of evidence analyses were focused on the level of the honeybee colony. These colony-level responses include redundancy and resiliency as well as a number of possible sublethal effects of pesticides on the colony. We also note that the literature has shown that binding of neonicotinoid insecticides to the nicotinic acetylcholine receptor is reversible. The comments in this letter do not provide reasons to change our conclusions, that, as currently used in good agricultural practices as seed-treatments, imidacloprid, clothianidin, and thiamethoxam do not present significant risks to honeybees at the level of the colony.

  • Risk assessment of benzalkonium chloride in cosmetic products
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2017-12-06
    Seul Min Choi, Tae Hyun Roh, Duck Soo Lim, Sam Kacew, Hyung Sik Kim, Byung-Mu Lee

    A risk assessment of benzalkonium chloride (BAC) was conducted based upon its toxicological profile and exposure evaluation. Since 1935, BAC has been used in a wide variety of products such as disinfectants, preservatives, and sanitizers. It is well-established that BAC is not genotoxic nor does it display tumorigenic potential, but safety concerns have been raised in local usage such as for ocular and intranasal applications. The Foundation of Korea Cosmetic Industry Institute (KCII) reported that in a hair conditioner manufactured as a cosmetic or personal product in South Korea, BAC was present at concentrations of 0.5–2%. The systemic exposure dosage (SED) was determined using the above in-use concentrations and a risk assessment analysis was conducted. The Margin of Safety (MOS) values for hair conditioners were calculated to be between 621 and 2,483. The risk of certain personal and cosmetic products was also assessed based upon assumptions that BAC was present at the maximal level of regulation in South Korea and that the maximal amount was used. The MOS values for the body lotion were all above 100, regardless of the application site. Collectively, data indicate that there are no safety concerns regarding use of products that contain BAC under the current concentration restrictions, even when utilized at maximal permitted levels. However, a chronic dermal toxicity study on BAC and comprehensive dermal absorption evaluation needs to be conducted to provide a more accurate prediction of the potential health risks to humans.

  • From Infections to Anthropogenic Inflicted Pathologies: Involvement of Immune Balance
    J. Toxicol. Environ. Health B Crit. Rev. (IF 6.436) Pub Date : 2017-12-18
    Florence Lee, David A Lawrence

    A temporal trend can be seen in recent human history where the dominant causes of death have shifted from infectious to chronic diseases in industrialized societies. Human influences in the current “Anthropocene” epoch are exponentially impacting the environment and consequentially health. Changing ecological niches are suggested to have created health transitions expressed as modifications of immune balance from infections inflicting pathologies in the Holocene epoch (12,000 years ago) to human behaviors inflicting pathologies beginning in the Anthropocene epoch (300 years ago). A review of human immune health and adaptations responding to environmental (biological, chemical, physical, and psychological) stresses, which are influenced by social conditions, emphasize the involvement of fluctuations in immune cell subsets affecting influential gene–environment interactions. The literature from a variety of fields (anthropological, immunological, and environmental) is incorporated to present an expanded perspective on shifts in diseases within the context of immune balance and function and environmental immunology. The influences between historical and contemporary human ecology are examined in relation to human immunity. Several examples of shifts in human physiology and immunity support the premise that increased incidences of chronic diseases are a consequence of human modification of environment and lifestyle. Although the development of better health care and a broader understanding of human health have helped with better life quality and expectancy, the transition of morbidity and mortality rates from infections to chronic diseases is a cause for concern. Combinations of environmental stressors/pollutants and human behaviors and conditions are modulating the immune-neuroendocrine network, which compromises health benefits.

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上海纽约大学William Glover