Chromium: a review of environmental and occupational toxicology

The following topics are covered in this brief review on the environmental and occupational toxicology of chromium: occurrence, production and uses of chromium and chromium compounds; experimental toxicology; chromium toxicity for man; hygienic and ecologic aspects of chromium contamination of the environment. The review provides a conclusive evidence which suggests that chromium, especially its hexavalent form, is both toxic and carcinogenic, but its trivalent form is physiologically essential in the metabolism of insulin. It is also emphasized that among the major sources of environmental chromium today are the cement industry and the increasingly widespread use of chromium compounds added as an anticorrosion admixture to a variety of cooling systems, e.g. in large power plants, which may greatly contribute to the overall pollution of outdoor air at the sites.     

Hygienic-toxicological aspects of exposure to lead. A critical review

This review on hygienic, toxicologic and ecologic aspects of environmental burden of lead deals with the following topics: occurrence, production and use of lead; metabolism of lead and experimental toxicology of lead; toxicity of lead to man; hygienic and ecologic aspects of lead pollution. Lead ore mining and processing, production of lead-acid batteries and combustion of gasoline containing tetraethyl-lead as an anti-knock ingredient constitute at present the most important sources of lead pollution. The last named source of lead pollution in urban atmosphere is most hazardous to human health. Attempts to reduce this health hazard include use of additive-free gasoline, or replacement of tetraethyl lead by other anti-knock agents, e. g. by tetraethylcopper. The experiments with the use of organic compounds of manganese have failed to succeed. The possibility of biological monitoring of occupational and nonoccupational exposures to lead is discussed in detail in this review.     

The Use of Epidemiology in Risk Assessment: Challenges and Opportunities

The assessment of risk from environmental and occupational exposures incorporates and synthesizes data from a variety of scientific disciplines including toxicology and epidemiology. Epidemiological data have offered valuable contributions to the identification of human health hazards, estimation of human exposures, quantification of the exposure–response relation, and characterization of risks to specific target populations including sensitive populations. As with any scientific discipline, there are some uncertainties inherent in these data; however, the best human health risk assessments utilize all available information, characterizing strengths and limitations as appropriate. Human health risk assessors evaluating environmental and occupational exposures have raised concerns about the validity of using epidemiological data for risk assessment due to actual or perceived study limitations. This article highlights three concerns commonly raised during the development of human health risk assessments of environmental and occupational exposures: (a) error in the measurement of exposure, (b) potential confounding, and (c) the interpretation of non-linear or non-monotonic exposure–response data. These issues are often the content of scientific disagreement and debate among the human health risk assessment community, and we explore how these concerns may be contextualized, addressed, and often ameliorated.     

Epidemiological Assessment of Hormesis in Studies with Low-Level Exposure

Despite its resurgence within toxicology and, specifically, risk assessment, the concept of hormesis remains peripheral to current epidemiological practice. In this paper we examine some reasons for this, focusing on applications within occupational and environmental epidemiology. Unclear in the existing literature is whether hormesis pertains to a single biological mechanism or response, or the aggregate effect of all correlates of exposure. Although J-shaped and U-shaped relationships between risk factors and disease endpoints have been identified epidemiologically, it is unclear whether such patterns reflect biological hormesis or a combination of factors resulting in a hormetic-looking relationship. Given the potential importance of assessing hormetic responses in epidemiological studies, we identify and discuss key limitations of epidemiology in validly detecting and interpreting hormesis. For example, most observational occupational and environmental studies lack the ability to determine the dose received by each individual, and therefore poor surrogates of exposure are frequently used, potentially introducing considerable systematic and random error. Further, because exposure is not randomly assigned to humans, the potential for confounding is great. Finally, using a simple simulation to assess the impact of ignoring hormesis in the analysis of epidemiological data containing mild hormesis, we demonstrate a resulting “hormetic bias,” in which relative risks at exposure levels above the hormetic region are systematically overestimated.     

Issues in Exposure and Dose Assessment for Epidemiology and Risk Assessment

Epidemiologic studies have been effective in identifying human environmental and occupational hazards. However, most epidemiologic data has been difficult to use in quantitative risk assessments because of the vague specification of exposure and dose. Toxicologic animal studies have used applied doses (quantities administered, or exposures with fixed duration) and well characterized end points to determine effects. However, direct use of animal data in human risk assessment has been limited by uncertainties in the extrapolation. The applied dose paradigm of toxicology is not suited for cross species extrapolation, nor for use in epidemiology as a dose metric because of the complexity of human exposures. Physiologically based pharmacokinetic (PBPK) modeling can estimate the time course of tissue concentrations in humans, given an exposure-time profile, and it has been used for extrapolating findings from animals to humans. It is proposed that human PBPK modeling can be used in appropriately designed epidemiologic studies to estimate tissue concentrations. Secondly, tissue time courses can be used to form dose metrics based on the type and time course of adverse effects. These dose metrics will strengthen the determination of epidemiologic dose-response relationships by reducing misclassification. Findings from this approach can be readily integrated into quantitative risk assessment.     

Considerations in Estimating Social and Economic Impacts of Immunotoxic Agents

To make appropriate regulatory policy decisions, the potential social and economic impacts of the policy must first be established. For environmental and occupational agents, social and economic impacts are derived from animal toxicology and, when available, human studies that serve as the base for risk-benefit analysis (RBA). Because immune function is associated with resistance to infectious disease, developing RBA for data derived from immunotoxicology studies will require determining the changes in the frequency or severity of infectious disease resulting from an exposure. Fortunately, considerable information is readily available for identifying the frequency of infectious diseases in the general population and its social and economic impacts and to assist the risk assessor when conducting RBA for immunotoxicology endpoints. The following is a brief review describing some issues in using immunotoxicity data when conducting RBA. It presents an economic methodology to determine the economic impacts of infectious diseases to society, sources where these types of information are available, and an example using a specific infectious disease, otitis media.     

Environmental mutagenesis and use of biomarkers in cancer risk prediction

The field of environmental mutagenesis or toxicology genetics aims to study the genetic damage that leads to mutations produced by physical, chemical and biological agents, to identify these agents and analyze their interactions and ways of action. There are enough experimental and epidemiological evidences implicating mutations in oncogenes, tumor suppressor genes and DNA repair genes as determinants in the onset and progression of the neoplastic process. A valuable tool in public and occupational health is the monitoring of populations exposed to potentially hazardous agents. The objective is to protect the health and quality of life of high risk groups on account of the nature of the agents of exposure. Monitoring of genotoxic effects in exposed populations as well as the analysis of susceptibility polymorphism are visualized as key tools in the realm of future public and occupational health in order to prevent the occurrence of environmental and specially occupational origin of tumors. This paper reviews the main concepts concerning this issue and refers to studies on the subject in Costa Rica.     

Epidemiology in protection and prevention against environmental mutagens/carcinogens Examples from occupational medicine

Subjects occupationally exposed to potential mutagens/carcinogens represent the most suitable groups for epidemiological studies aimed at assessing the risk for the individual or the offspring. Several cancer risks to humans have been detected by epidemiological studies performed in occupational settings. Cancer epidemiology studies have been able (a) to identify specific occupations or agents associated with the risk; (b) to verify the results of experimental studies; (c) to test the effectiveness of changes in production or preventive measures in decreasing risks. Reproductive epidemiology has suggested a risk of spontaneous abortions or of malformation in the offspring of workers exposed to some chemicals or occupations, but data are often conflicting due to methodological problems. With the aim of early assessment of risk in mind, the epidemiological use of indicators of exposure or of the early effect of exposure to genotoxic agents is increasingly applied to occupational groups. Cytological monitoring of subjects at risk of occupational cancer of lung or bladder is carried out mainly to diagnose precancerous lesions of target tissues. Cytogenetic methods (chromosome aberrations, SCE, micronuclei) in somatic cells provide a means for detecting early effects of occupational exposure to known or potential mutagens/carcinogens in selected groups of individuals, but their significance is widely debated. Monitoring of urinary mutagenicity, as applied in nurses handling cytostatic drugs, is an example of how an indicator of exposure to genotoxins can be used to evaluate the impact of preventive measures. Among the perspectives, biochemical epidemiology seems to be promising in detecting individuals genetically susceptible to cancer.     

The toxicology of mercury and its compounds

A concentrated review on the toxicology of inorganic mercury together with an extensive review on the neurotoxicology of methylmercury is presented. The challenges of using inorganic mercury in dental amalgam are reviewed both regarding the occupational exposure and the possible health problems for the dental patients. The two remaining “mysteries” of methylmercury neurotoxicology are also being reviewed; the cellular selectivity and the delayed onset of symptoms. The relevant literature on these aspects has been discussed and some suggestions towards explaining these observations have been presented.     

Challenges and Research Needs for Risk Assessment of Pesticides for Registration in Africa

Risk assessment is necessary for registration and risk management of new pesticides. The aim of this article is to discuss challenges that risk assessors in Africa face when conducting risk assessment of pesticides. Risk assessment requires toxicity assessment, environmental fate studies, and the use of models for occupational, dietary, residential, and environmental exposure assessments. Toxicity studies are very costly with the result that toxicity data used to register pesticides in Africa are often sourced from northern hemisphere countries. Assessors also often use exposure modeling results from the northern hemisphere. This is not an ideal approach as occupational exposure is influenced by agricultural practices, climatic conditions, and other factors. Furthermore, residential exposure models require time-location-activity information, exposure factors, and toxicokinetic rate constants for particular pesticides. Dietary exposure assessment needs accurate and comprehensive local food consumption data. Authorities in African countries should therefore generate the required data, despite these being very costly and tedious. Authorities should also provide guidance on the type of models and standard scenarios for estimating predicted environmental concentrations in various environmental compartments. It is recommended that higher educational institutions in Africa should incorporate risk assessment in general and pesticide toxicity and exposure models in particular in their curricula.     

Human stem cells, chromatin, and tissue engineering: boosting relevancy in developmental toxicity testing

Risk assessment derives its confidence from toxicology research that is based on relevancy to human health. This article focuses on two highly topical areas of current scientific research, stem cells and chromatin biology, which present new avenues for preclinical and clinical applications, and the frontier role of tissue engineering and regeneration. Appreciating the utility and necessity of chromatin and human somatic stem cells as research tools and looking toward tissue engineering may close the uncertainty gaps between animal and human cross-species toxicology evaluations. The focus will be on developmental toxicology applications, but appropriate extrapolation to any other areas of toxicology can be made. We further provide background on basic biology of these three areas and examples of how early life exposure to known and potential environmental toxicants induce malformations, childhood and adult-onset diseases, through aberrant chromatin modification of critical gene expressions (acute lymphocyte leukemia, heavy-metal nickel and cadmium-associated defects, and reproductive tract malformations and carcinomas induced by the synthetic estrogen, diethylstilbestrol).     

Assessment of Human Health and Ecological Risks Posed by the Uses of Steel-Industry Slags in the Environment

Steel-industry slag, a co-product of iron and steel production, is produced and sold for use in a wide range of applications. A comprehensive study of the potential human health risks associated with the environmental applications (e.g., fill, roadbase, landscaping) of iron- and steel-making slag was performed using characterization data for 73 samples of slag collected from blast furnaces, basic oxygen furnaces, and electric arc furnaces. Characterization data were compared to regulatory health-based “screening” benchmarks to determine constituents of interest. Antimony, beryllium, cadmium, trivalent and hexavalent chromium, manganese, thallium, and vanadium were measured above screening levels and were assessed in an application-specific exposure assessment using standard U.S. Environmental Protection Agency risk assessment methods. A stochastic analysis was conducted to evaluate the variability and uncertainty in the inhalation exposure and risk estimates, and the oral bioaccessibility of certain metals in the slag was quantified. The risk assessment found no significant hazards to human health as a result of the environmental applications of steel-industry slag. However, site-specific ecological risk assessment may be required for slag applications in and around small water bodies with limited dilution volume, because high pH and aluminum were found to leach at levels that may be harmful to aquatic life     

The impact of new technologies on human population studies

Human population studies involve clinical or epidemiological observations that associate environmental exposures with health endpoints and disease. Clearly, these are the most sought after data to support assessments of human health risk from environmental exposures. However, the foundations of many health risk assessments rest on experimental studies in rodents performed at high doses that elicit adverse outcomes, such as organ toxicity or tumors. Using the results of human studies and animal data, risk assessors define the levels of environmental exposures that may lead to disease in a portion of the population. These decisions on potential health risks are frequently based on the use of default assumptions that reflect limitations in our scientific knowledge. An important immediate goal of toxicogenomics, including proteomics and metabonomics, is to offer the possibility of making decisions affecting public health and public based on detailed toxicity, mechanistic, and exposure data in which many of the uncertainties have been eliminated. Ultimately, these global technologies will dramatically impact the practice of public health and risk assessment as applied to environmental health protection. The impact is already being felt in the practice of toxicology where animal experimentation using highly controlled dose-time parameters is possible. It is also being seen in human population studies where understanding human genetic variation and genomic reactions to specific environmental exposures is enhancing our ability to uncover the causes of variations in human response to environmental exposures. These new disciplines hold the promise of reducing the costs and time lines associated with animal and human studies designed to assess both the toxicity of environmental pollutants and efficacy of therapeutic drugs. However, as with any new science, experience must be gained before the promise can be fulfilled. Given the numbers and diversity of drugs, chemicals and environmental agents; the various species in which they are studied and the time and dose factors that are critical to the induction of beneficial and adverse effects, it is only through the development of a profound knowledge base that toxicology and environmental health can rapidly advance. The National Institute of Environmental Health Sciences (NIEHS), National Center for Toxicogenomics and its university-based Toxicogenomics Research Consortium (TRC), and resource contracts, are engaged in the development, application and standardization of the science upon which to the build such a knowledge base on Chemical Effects in Biological Systems (CEBS). In addition, the NIEHS Environmental Genome Project (EGP) is working to systematically identify and characterize common sequence polymorphisms in many genes with suspected roles in determining chemical sensitivity. The rationale of the EGP is that certain genes have a greater than average influence over human susceptibility to environmental agents. If we identify and characterize the polymorphism in those genes, we will increase our understanding of human disease susceptibility. This knowledge can be used to protect susceptible individuals from disease and to reduce adverse exposure and environmentally induced disease.     

Biomarkers in risk assessment of asbestos exposure

Developments in the field of molecular epidemiology and toxicology have given valuable tools for early detection of impending disease or toxic condition. Morbidity due to respiratory distress, which may be due to environmental and occupational exposure, has drawn attention of researchers worldwide. Among the occupational exposure to respiratory distress factors, fibers and particles have been found to be main culprits in causing diseases like asbestosis, pleural plaques, mesotheliomas and bronchogenic carcinomas. An early detection of the magnitude of exposure or its’ effect using molecular end points is of growing importance. The early inflammatory responses like release of the inflammatory cells collected by non-invasive methods give an indication of the unwanted exposure and susceptibility to further complications. Since free radicals like O₂⁻, OH, OOH, NO, NOO, etc. are involved in the progression of asbestos-related diseases and lead to cytogenetic changes, an evaluation of antioxidant states reducing equivalents like GSH and ROS generation can be a good biomarker. The cytogenetic end points like chromosomal aberration, micronucleus formation and sister chromatid exchange give indication of genetic damage, hence they are used as effective biomarkers. New techniques like fluorimetric analysis of DNA unwinding, alkaline elution test, fluorescent in situ hybridization and comet assay are powerful tools for early detection of initiation of disease process and may help in planning strategies for minimizing morbidity related to asbestos fiber exposure. The present review article covers in detail possible biomarkers for risk assessment of morbidity due to fibers/particles in exposed population.     

FT-IR spectroscopy as a tool for rapid identification and intra-species characterization of airborne filamentous fungi

Identification of microfungi is time-consuming due to cultivation and microscopic examination and can be influenced by the interpretation of the macro- and micro-morphological characters observed. Fungal conidia contain mycotoxins that may be present in bioaerosols and thus the capacity for production of mycotoxins (and allergens) needs to be investigated to create a basis for reliable risk assessment in environmental and occupational hygiene. The present investigation aimed to create a simple but sophisticated method for the preparation of samples and the identification of airborne fungi by FT-IR spectroscopy. The method was suited to reproducibly differentiate Aspergillus and Penicillium species on the generic, the species, and the strain level. There are strong indications that strains of one taxon differing in metabolite production can be reliably distinguished by FT-IR spectroscopy (e.g. Aspergillus parasiticus). On the other hand, species from different taxa being similar in secondary metabolite production showed comparably higher similarities. The results obtained here can serve as a basis for the development of a database for species identification and strain characterization of microfungi. The method presented here will improve and facilitate the risk assessment in case of bioaerosol exposure, as strains with different physiological properties (e.g. toxic, non-toxic) could be differentiated. Moreover, it has the potential to significantly improve the identification of microfungi in various fields of applied microbiological research, e.g. high throughput screening in view of specific physiological properties, biodiversity studies, inventories in environmental microbiology, and quality control measures.     

Mercapturic acids as biomarkers of exposure to electrophilic chemicals:applications to environmental and industrial chemicals

The use of mercapturic acids (N-acetyl-L-cysteine S-conjugates, MAs) in the biological monitoring of human exposure to environmental and industrial chemicals is receiving more and more attention. Mercapturic acids (MAs) are formed from glutathione (GSH) S-conjugates via the MA-pathway. Although this pathway can lead to different end-products, the formation of MAs is the predominant route in most species, including man. Two GSH S-transferases (GSTs) show genetic polymorphisms in humans and this can have major consequences for individual susceptibility to toxic effects and for MA formation. In occupational toxicology, adducts to biomacromolecules are also used as biomarkers. DNA adducts are a measure for the effective dose, while protein adducts are related to the dose at critical site. Both type of adducts are normally determined in blood, while MAs are determined in urine. Most MAs are excreted with relatively short half-lifes, allowing a direct evaluation of the occupational circumstances. For many compounds similar (linear) dose-dependency was found for MA excretion, formation of macromolecular adducts, and for various biomarkers of toxic effects. These relations together with fact that MAs relate to the electrophilic character of compounds, allows for the conclusion that MAs are biomarkers of toxicologically relevant internal doses of chemicals or their metabolites. An overview will be given here of the use of MAs in the assessment of internal human exposure to electrophilic environmental and industrial chemicals. Additionally, the formation of GSH S-conjugates, their catabolism to MAs and several of the frequently used analytical approaches are discussed. When appropriate, the influence of genetic polymorphisms on formation of MAs and on susceptibility to toxicity will be discussed for different chemicals as well.     

Mercapturic acids as biomarkers of exposure to electrophilic chemicals:applications to environmental and industrial chemicals

The use of mercapturic acids (N-acetyl-L-cysteine S-conjugates, MAs) in the biological monitoring of human exposure to environmental and industrial chemicals is receiving more and more attention. Mercapturic acids (MAs) are formed from glutathione (GSH) S-conjugates via the MA-pathway. Although this pathway can lead to different end-products, the formation of MAs is the predominant route in most species, including man. Two GSH S-transferases (GSTs) show genetic polymorphisms in humans and this can have major consequences for individual susceptibility to toxic effects and for MA formation. In occupational toxicology, adducts to biomacromolecules are also used as biomarkers. DNA adducts are a measure for the effective dose, while protein adducts are related to the dose at critical site. Both type of adducts are normally determined in blood, while MAs are determined in urine. Most MAs are excreted with relatively short half-lifes, allowing a direct evaluation of the occupational circumstances. For many compounds similar (linear) dose-dependency was found for MA excretion, formation of macromolecular adducts, and for various biomarkers of toxic effects. These relations together with fact that MAs relate to the electrophilic character of compounds, allows for the conclusion that MAs are biomarkers of toxicologically relevant internal doses of chemicals or their metabolites. An overview will be given here of the use of MAs in the assessment of internal human exposure to electrophilic environmental and industrial chemicals. Additionally, the formation of GSH S-conjugates, their catabolism to MAs and several of the frequently used analytical approaches are discussed. When appropriate, the influence of genetic polymorphisms on formation of MAs and on susceptibility to toxicity will be discussed for different chemicals as well.     

Future directions in butadiene risk assessment and the role of cross-species internal dosimetry

The 2005 International Symposium on the evaluation of butadiene and chloroprene health risks provided the opportunity to consider the past, present and future state of research issues for 1,3-butadiene. Considerable advancements have been made in our knowledge of exposure, metabolism, biomarkers of exposure and effect, and epidemiology. Despite this, uncertainties remain which will impact the human health risk assessment for current worker and environmental exposures. This paper reviews key aspects of recent studies and the role that biomarkers of internal dosimetry can play in addressing low to high exposure, gender, and cross-species differences in butadiene toxicity and metabolism. Considerable information is now available on the detection and quantification of protein adducts formed from the mono-, di- and dihydroxy-epoxide metabolites of butadiene. The diepoxide metabolite appears to play a key role in mutagenesis. Species differences in production of this critical metabolite are reflected by the diepoxybutane-specific hemoglobin adduct, pry-Val. To date, the pry-Val adduct has not been quantifiable in human blood samples from workers with cumulative occupational exposures up to 6.3 ppm-weeks; whereas, the pry-Val was quantifiable in the blood of mice and rats with similar cumulative exposures. Levels in mice were much higher than in rats. Further improvements in analytical sensitivity for the pyr-Val adduct are on the horizon. Epidemiology studies are also described and ongoing efforts promise to help bridge our understanding of past and future risks.     

From quantal counts to mechanisms and systems: the past, present, and future of biometrics in environmental toxicology

As appreciation for human impact on the environment has developed, so have the experimental systems and associated statistical tools that quantify this impact. Toxicological study in particular has grown in its complexity and its need for advanced statistical support. Within this perspective, we describe statistical practice in environmental toxicology and risk assessment. We present two case studies, one from mammalian toxicology and one from aquatic toxicology, that highlight the evolution of statistical practice in environmental toxicology.     

Intensity-time dependence dosing criterion in the EMF exposure guidelines in Russia

Major approaches of the Russian Federation in setting of exposure guidelines to electromagnetic fields (EMF) in occupational and public environments are discussed in this paper.

EMF exposure guidelines in Russia are based on the results of hygienic, clinical, physiological, epidemiological and experimental studies and are frequency-dependent. The concept of a threshold principle of occupational and environmental factors due to hazardous exposure effects has been used to set permissible exposure levels of different EMF frequency ranges. The data of experimental studies showed hazardous threshold levels of EMF effects. The main criteria of EMF hazardous exposure evaluated in the experimental study concerned both estimation of threshold levels of chronic (long-term) and acute exposure. Also, this paper contains some recent experimental study data on correlation of long-term radiofrequency and power-frequency EMF exposure effects with regard to time duration, the so-called time-dependence approach. It enables identification of the value of permissible EMF exposure levels depending on exposure duration. This approach is used in occupational exposure guideline setting and requires the introduction of “power exposition” (PE) and “maximal permissible level” (MPL). In general, EMF exposure guidelines are established with regard to possible duration of exposure per day.