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1.  Finding toxicological information: An approach for occupational health professionals 
Background
It can be difficult for occupational health professionals to assess which toxicological databases available on the Internet are the most useful for answering their questions. Therefore we evaluated toxicological databases for their ability to answer practical questions about exposure and prevention. We also propose recommended practices for searching for toxicological properties of chemicals.
Methods
We used a systematic search to find databases available on the Internet. Our criteria for the databases were the following: has a search engine, includes factual information on toxic and hazardous chemicals harmful for human health, and is free of charge. We developed both a qualitative and a quantitative rating method, which was used by four independent assessors to determine appropriateness, the quality of content, and ease of use of the database. Final ratings were based on a consensus of at least two evaluators.
Results
Out of 822 results we found 21 databases that met our inclusion criteria. Out of these 21 databases 14 are administered in the US, five in Europe, one in Australia, and one in Canada. Nine are administered by a governmental organization. No database achieved the maximum score of 27. The databases GESTIS, ESIS, Hazardous Substances Data Bank, TOXNET and NIOSH Pocket Guide to Chemical Hazards all scored more than 20 points. The following approach was developed for occupational health professionals searching for the toxicological properties of chemicals: start with the identity of the chemical; then search for health hazards, exposure route and measurement; next the limit values; and finally look for the preventive measures.
Conclusion
A rating system of toxicological databases to assess their value for occupational health professionals discriminated well between databases in terms of their appropriateness, quality of information, and ease of use. Several American and European databases yielded high scores and provide a valuable source for occupational health professionals.
doi:10.1186/1745-6673-3-18
PMCID: PMC2551601  PMID: 18700959
2.  A carbamate insecticide: a case study of aldicarb. 
Environmental Health Perspectives  1994;102(Suppl 11):23-27.
Aldicarb, the active ingredient in the insecticide TEMIK, was introduced to the agricultural community over 25 years ago. It has been registered worldwide to control a wide variety of insect, mite, and nematode pests in agriculture. The toxicological research database supporting the registration and use of aldicarb was generated over more than 25 years and contains more than 280 animal studies on 12 species of animals, 2 clinical human trials, and over 20 human monitoring studies. This database, which includes biochemical aspects (metabolism and mode-of-action studies), acute toxicity and special short-term toxicity studies, long-term toxicity studies, and epidemiological observations in humans, serves as the starting point for the evaluation of the risks associated with the acceptance of levels of aldicarb residues in food and drinking water and for the more direct occupational exposure. This article highlights the available toxicological data and reviews worldwide regulation of aldicarb. Included in these discussions is a brief description of the toxicological end point upon which regulatory decisions have been based, namely acetylcholinesterase depression. Aldicarb, the N-methylcarbamic acid ester of 2-methyl-2-(methylthio) propionaldehyde oxime, was the first of a limited group of insecticidal oxime N-methylcarbamates that have properties distinct from N-methylcarbamates which have a phenolic constituent, instead of the oxime moiety. Aldicarb is highly water-soluble (approximately 6000 ppm), nonvolatile, relatively stable under acidic conditions, and is easily degraded under alkaline conditions. These properties are important determinants of its systemic action in plants and of its problematic environmental behavior. Possible environmental hazards involving the chemical include groundwater contamination and (more recently) excessive terminal residues in certain foods.
PMCID: PMC1566767  PMID: 7737038
3.  Occupational safety and health criteria for responsible development of nanotechnology 
Organizations around the world have called for the responsible development of nanotechnology. The goals of this approach are to emphasize the importance of considering and controlling the potential adverse impacts of nanotechnology in order to develop its capabilities and benefits. A primary area of concern is the potential adverse impact on workers, since they are the first people in society who are exposed to the potential hazards of nanotechnology. Occupational safety and health criteria for defining what constitutes responsible development of nanotechnology are needed. This article presents five criterion actions that should be practiced by decision–makers at the business and societal levels—if nanotechnology is to be developed responsibly. These include (1) anticipate, identify, and track potentially hazardous nanomaterials in the workplace; (2) assess workers’ exposures to nanomaterials; (3) assess and communicate hazards and risks to workers; (4) manage occupational safety and health risks; and (5) foster the safe development of nanotechnology and realization of its societal and commercial benefits. All these criteria are necessary for responsible development to occur. Since it is early in the commercialization of nanotechnology, there are still many unknowns and concerns about nanomaterials. Therefore, it is prudent to treat them as potentially hazardous until sufficient toxicology, and exposure data are gathered for nanomaterial-specific hazard and risk assessments. In this emergent period, it is necessary to be clear about the extent of uncertainty and the need for prudent actions.
doi:10.1007/s11051-013-2153-9
PMCID: PMC3890581  PMID: 24482607
Risk assessment; Ethics; Risk management; Regulation; Toxicology; Environmental and health effects
4.  Toxicological Evaluations of Rare Earths and Their Health Impacts to Workers: A Literature Review 
Safety and Health at Work  2013;4(1):12-26.
In concert with the development of new materials in the last decade, the need for toxicological studies of these materials has been increasing. These new materials include a group of rare earths (RE). The use of RE nanotechnology is being considered in some green applications, to increase their efficiency by using nano-sized RE compounds, and therefore hazard evaluation and risk assessment are highly recommended. This review was conducted through an extensive contemplation of the literatures in toxicology with in vitro and in vivo studies. Major aspects reviewed were the toxicological evaluations of these elements and metallic compounds at the molecular and cellular level, animal and human epidemiological studies and environmental and occupational health impacts on workers. We also discuss the future prospect of industries with appliances using RE together with the significance of preventive efforts for workers' health. To establish a safe and healthy working environment for RE industries, the use of biomarkers is increasing to provide sustainable measure, due to demand for information about the health risks from unfavorable exposures. Given the recent toxicological results on the exposure of cells, animals and workers to RE compounds, it is important to review the toxicological studies to improve the current understanding of the RE compounds in the field of occupational health. This will help to establish a sustainable, safe and healthy working environment for RE industries.
doi:10.5491/SHAW.2013.4.1.12
PMCID: PMC3601293  PMID: 23516020
Rare earths; Toxicology; Environmental health; Occupational health
5.  Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing 
PLoS Medicine  2014;11(4):e1001628.
Gary Peltz, Jeffrey Glenn, and colleagues report that a pre-clinical mouse toxicology model can detect liver toxicity of a drug that caused liver failure in several early clinical trial participants in 1993.
Please see later in the article for the Editors' Summary
Background
Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.
Methods and Findings
Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers.
Conclusions
FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Before new drugs are approved for clinical use, they undergo extensive preclinical (laboratory-based) and clinical testing. In the preclinical studies, scientists investigate the causes of diseases, identify potential new drugs, and test promising drug candidates in animals. Animal testing is performed to determine whether the new drug is likely to work, and to screen for drug-induced toxicity. In preclinical toxicology studies, new drugs are given to two or more animal species to find out whether the drug has any short- or long-term toxic effects such as damage to the liver (hepatotoxicity). Drugs that pass these animal tests enter clinical trials. Phase I clinical trials test new drugs in a handful of healthy volunteers or patients to evaluate their safety and to identify possible side effects. In phase II trials, a larger group of patients receives the new drug to evaluate its safety further and to get an initial idea of its effectiveness. Finally, in phase III trials, very large groups of patients are randomly assigned to receive the new drug or an established treatment for their disease. These randomized controlled trials provide detailed information about the effectiveness and safety of a candidate drug, and must be completed before a drug can be approved for clinical use.
Why Was This Study Done?
Since animals are not perfect models for people, candidate drugs can cause toxicities in clinical trials that were not predicted by preclinical toxicology testing performed using animal species. For example, in 1993, 15 participants in a phase II trial were given a nucleoside analogue called fialuridine to treat hepatitis B virus infection (nucleoside analogues often have antiviral activity). Seven participants developed liver failure and lactic acidosis (buildup of lactic acid in the blood). Analysis of liver tissue from the affected participants revealed steatosis (fatty degeneration), intracellular fat droplets, and swollen mitochondria (these organelles are the powerhouses of the cell). Five participants subsequently died, and two had to have a liver transplant. In preclinical toxicology testing in mice, rats, dogs, and primates, there had been no indications that fialuridine would be hepatotoxic in people. It now seems that the expression of a nucleoside transporter in the mitochondria of humans but not of other animals may underlie the human-specific mitochondrial toxicity and hepatotoxicity of fialuridine. With several other nucleoside analogues in development, a better screening tool for human-specific mitochondrial toxicity is needed. In this study, the researchers investigate whether fialuridine toxicity can be detected in TK-NOG mice with chimeric (humanized) livers. TK-NOG mice are immunodeficient mice that have been genetically engineered so that human liver cells (hepatocytes) transplanted into these animals establish a long-lived mature “human organ.”
What Did the Researchers Do and Find?
The researchers treated chimeric (with transplanted human liver cells) and control (without transplanted human liver cells) TK-NOG mice with several doses of fialuridine. After treatment with the highest dose (1,600-fold above the dose used in the phase II trial) for four days, the chimeric mice developed liver failure and lactic acidosis. Moreover, steatosis and lipid and mitochondrial abnormalities developed in the regions of their livers that contained human hepatocytes but not in regions that contained mouse hepatocytes. Notably, the control mice had not developed liver toxicity after 14 days of treatment with the highest dose of drug. Liver toxicity was also easily detectable in chimeric mice that had been treated for 14 days with a fialuridine dose only 10-fold above that used in the human trial. Treatment with another nucleoside analogue that does not cause liver toxicity in people did not cause liver toxicity in the chimeric mice.
What Do These Findings Mean?
These findings show that fialuridine-induced liver toxicity can be readily detected using TK-NOG mice that have humanized livers at drug doses only 10-fold higher than those that caused liver failure in the phase II trial. Although the liver toxicity developed much more quickly in these mice than in the human trial participants, the clinical features, laboratory abnormalities, and structural changes seen in the fialuridine-treated chimeric TK-NOG mice closely mirrored those seen in fialuridine-treated people. The use of TK-NOG mice containing humanized livers in toxicology testing will not reveal whether drugs have human-specific toxicities outside the liver. Since they are highly immunocompromised, chimeric TK-NOG mice cannot be used to detect immune-mediated drug toxicities. Nevertheless, these findings suggest that the use of chimeric mice in toxicology studies could help improve the safety of candidate drugs that are tested in humans.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001628.
The US Food and Drug Administration, the body that approves drugs for clinical use in the US, provides an overview for patients about the drug development process from the laboratory to the clinic
The UK Medicines and Healthcare Products Regulatory Agency (MHRA) provides more detailed information for patients and the public about the drug development process, including a section on preclinical research, which includes information on animal testing
The US National Institutes of Health provides information about clinical trials, including personal stories from people who have taken part in clinical trials
The UK National Health Service Choices website has information for patients about clinical trials and medical research, including personal stories about participation in clinical trials
Understanding Animal Research is a UK advocacy group that provides information about the importance of animal research to the public, teachers, scientists, journalists, and policy makers
Wikipedia has a page on animal testing (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001628
PMCID: PMC3988005  PMID: 24736310
6.  AB 9. Health management of occupational diseases challenge for the bulgarian economy and public health 
Journal of Thoracic Disease  2012;4(Suppl 1):AB9.
Background
In 2001 a National Registry of Occupational Diseases was founded in Bulgaria which introduced a new system of reporting and recording Occupational illness into practice. In 2009 more than 400,000 people in Bulgaria were recorded with permanent disability, a lot of them representing victims of Occupational illness or injury. The intention of our present study was to analyze the frequency and type of different Occupational diseases over the last decade, and to determine which types of employment represent the greatest Occupational hazards to the employees’ health and safety.
Patients and methods
A detailed and thorough record of patients with Occupational illnesses was collected by experts for the mentioned time frame. An analysis of the health information was conducted and the characteristics and hazards at the work place were identified. The type and frequency of different Occupational illnesses were investigated and the Occupational Hazards and their effects on employment were determined.
Results
From 1998 until 2008 the number of Occupational diseases in Bulgaria increased especially in specific areas of employment. Musculoskeletal diseases and peripheral nerve-damage caused by exposure to hazardous substances at the workplace represent 55% of all cases. While respiratory diseases (like chronic bronchitis, COPD and bronchiectasis) and diseases caused by noise and vibrations comprise 22% and 12% of cases, accordingly.
Conclusions
The number of patients with permanent disability in Bulgaria is extremely high - which is unacceptable from the medical, social and economic point of view. This is the result of changes of Occupational dynamics (the aging work-population, immigration) and unfavorable work conditions at a time of economic transition. Contributory are also changes of law and practice of Occupational Medicine as well as insufficient training and information of employees about Occupational health and safety. It is important to improve the training of Occupational Physicians which will facilitate preventative and early diagnostic measures of Occupational illnesses and thus substantially contribute to the improvement of Occupational conditions especially regarding serious Occupational hazards. This process needs to be well coordinated and in collaboration with all the parties responsible for the Occupational Health and Safety of employees. (This study was sponsored by “Proekt GRANT” 2012, of the Medical University of Sofia - Bulgaria.)
doi:10.3978/j.issn.2072-1439.2012.s009
PMCID: PMC3537354
7.  Health effects research and regulation of diesel exhaust: an historical overview focused on lung cancer risk 
Inhalation Toxicology  2012;24(s1):1-45.
The mutagenicity of organic solvent extracts from diesel exhaust particulate (DEP), first noted more than 55 years ago, initiated an avalanche of diesel exhaust (DE) health effects research that now totals more than 6000 published studies. Despite an extensive body of results, scientific debate continues regarding the nature of the lung cancer risk posed by inhalation of occupational and environmental DE, with much of the debate focused on DEP. Decades of scientific scrutiny and increasingly stringent regulation have resulted in major advances in diesel engine technologies. The changed particulate matter (PM) emissions in “New Technology Diesel Exhaust (NTDE)” from today's modern low-emission, advanced-technology on-road heavy-duty diesel engines now resemble the PM emissions in contemporary gasoline engine exhaust (GEE) and compressed natural gas engine exhaust more than those in the “traditional diesel exhaust” (TDE) characteristic of older diesel engines. Even with the continued publication of epidemiologic analyses of TDE-exposed populations, this database remains characterized by findings of small increased lung cancer risks and inconsistent evidence of exposure-response trends, both within occupational cohorts and across occupational groups considered to have markedly different exposures (e.g. truckers versus railroad shopworkers versus underground miners). The recently published National Institute for Occupational Safety and Health (NIOSH)-National Cancer Institute (NCI) epidemiologic studies of miners provide some of the strongest findings to date regarding a DE-lung cancer association, but some inconsistent exposure-response findings and possible effects of bias and exposure misclassification raise questions regarding their interpretation. Laboratory animal studies are negative for lung tumors in all species, except for rats under lifetime TDE-exposure conditions with durations and concentrations that lead to'lung overload."The species specificity of the rat lung response to overload, and its occurrence with other particle types, is now well-understood. It is thus generally accepted that the rat bioassay for inhaled particles under conditions of lung overload is not predictive of human lung cancer hazard. Overall, despite an abundance of epidemiologic and experimental data, there remain questions as to whether TDE exposure causes increased lung cancers in humans. An abundance of emissions characterization data, as well as preliminary toxicological data, support NTDE as being toxicologically distinct from TDE. Currently, neither epidemiologic data nor animal bioassay data yet exist that directly bear on NTDE carcinogenic potential. A chronic bioassay of NTDE currently in progress will provide data on whether NTDE poses a carcinogenic hazard, but based on the significant reductions in PM mass emissions and the major changes in PM composition, it has been hypothesized that NTDE has a low carcinogenic potential. When the International Agency for Research on Cancer (IARC) reevaluates DE (along with GEE and nitroarenes) in June 2012, it will be the first authoritative body to assess DE carcinogenic health hazards since the emergence of NTDE and the accumulation of data differentiating NTDE from TDE.
doi:10.3109/08958378.2012.691913
PMCID: PMC3423304  PMID: 22663144
Diesel exhaust; diesel emissions; lung cancer; new technology diesel exhaust (NTDE); epidemiology; mechanism; lung overload; elemental carbon; particulate matter; diesel particulate filter (DPF)
8.  Primary prevention and precaution in hazard identification in the NIEHS/NTP: body in the morgue approach. 
Public Health Reports  2002;117(6):564-573.
In the spirit of stimulating reevaluation of the methods of public health science, this article explores the methods of cancer hazard identification at the National Toxicology Program (NTP) from the perspective of primary prevention and precaution. The NTP is a cooperative effort of three federal agencies: The National Institute of Environmental Health Sciences (NIEHS, the lead government institute); the National Institute for Occupational Health (NIOSH), in the Centers for Disease Control and Prevention; and the National Center for Toxicology Research (NCTR), in the Food and Drug Administration. NTP coordinates toxicological research and testing programs within the Department of Health and Human Services (DHHS), and through its annual Report on Carcinogens (RoC), identifies and characterizes cancer hazards-the first step in quantitative risk assessment-for the federal government. The foundation of NIEHS policies, for environmental health research, is quantitative risk assessment (QRA). The author examines the opportunities for primary prevention and precaution, and the extent to which the policies of NIEHS in general, and the NTP in particular, do and do not realize that potential. Special attention is paid to the issue of cancer hazard identification. Critical comments on the process of classifying carcinogens in the Ninth and Tenth Reports on Carcinogens are presented, based on the minutes of the Board of Scientific Counselors Subcommittee meetings.
PMCID: PMC1497487  PMID: 12576536
9.  Toxicological Properties of the Organophosphorus Insecticide Dimethoate 
The results are presented of extensive toxicological studies on the systemic organophosphate insecticide dimethoate, and compared with published results from other laboratories. It behaves as a typical indirect anticholinesterase, by conversion in the liver to at least four short-lived active metabolites, whose hydrolysis products are rapidly excreted, mainly in the urine. The acute oral toxicity of dimethoate is low in mammals but higher in avians. Dermal absorption is notably slow and dermal toxicity correspondingly low. Cumulative dosing of rats and guinea-pigs gave no cholinesterase inhibition at 0·7 and 4 mg./kg./day respectively. Dietary feeding to growing rats caused no cholinesterase inhibition at 0·5 mg./kg./day and no other effect at 10 times this dose. The main plant metabolite is identical with one formed in the liver, and comparative feeding tests with normal dimethoate and that partly metabolized in vegetation showed that residue analysis determined total hazard. Tests on humans, some with 32P-labelled material, confirmed that metabolism and urinary excretion are very rapid, that skin absorption is very slow, and that at least 2·5 mg., and probably up to 18 mg., could be ingested daily for at least three weeks without cholinesterase inhibition or other effects. Vapour hazards proved negligible. Oral toxicity was not potentiated by any of 17 other insecticides. The earliest detectable effect of dimethoate poisoning was always erythrocyte cholinesterase inhibition. Symptoms of poisoning could be effectively treated by atropine but not by oxime therapy. No known cases of occupational poisoning have occurred during five years' commercial usage of dimethoate.
PMCID: PMC1039191  PMID: 14106136
10.  Drug delivery and nanoparticles: Applications and hazards 
The use of nanotechnology in medicine and more specifically drug delivery is set to spread rapidly. Currently many substances are under investigation for drug delivery and more specifically for cancer therapy. Interestingly pharmaceutical sciences are using nanoparticles to reduce toxicity and side effects of drugs and up to recently did not realize that carrier systems themselves may impose risks to the patient. The kind of hazards that are introduced by using nanoparticles for drug delivery are beyond that posed by conventional hazards imposed by chemicals in classical delivery matrices. For nanoparticles the knowledge on particle toxicity as obtained in inhalation toxicity shows the way how to investigate the potential hazards of nanoparticles. The toxicology of particulate matter differs from toxicology of substances as the composing chemical(s) may or may not be soluble in biological matrices, thus influencing greatly the potential exposure of various internal organs. This may vary from a rather high local exposure in the lungs and a low or neglectable exposure for other organ systems after inhalation. However, absorbed species may also influence the potential toxicity of the inhaled particles. For nanoparticles the situation is different as their size opens the potential for crossing the various biological barriers within the body. From a positive viewpoint, especially the potential to cross the blood brain barrier may open new ways for drug delivery into the brain. In addition, the nanosize also allows for access into the cell and various cellular compartments including the nucleus. A multitude of substances are currently under investigation for the preparation of nanoparticles for drug delivery, varying from biological substances like albumin, gelatine and phospholipids for liposomes, and more substances of a chemical nature like various polymers and solid metal containing nanoparticles. It is obvious that the potential interaction with tissues and cells, and the potential toxicity, greatly depends on the actual composition of the nanoparticle formulation. This paper provides an overview on some of the currently used systems for drug delivery. Besides the potential beneficial use also attention is drawn to the questions how we should proceed with the safety evaluation of the nanoparticle formulations for drug delivery. For such testing the lessons learned from particle toxicity as applied in inhalation toxicology may be of use. Although for pharmaceutical use the current requirements seem to be adequate to detect most of the adverse effects of nanoparticle formulations, it can not be expected that all aspects of nanoparticle toxicology will be detected. So, probably additional more specific testing would be needed.
PMCID: PMC2527668  PMID: 18686775
drug delivery; cancer therapy; nanoparticles; toxicology; pharmaceuticals
11.  Toxicogenomic profiling of chemically exposed humans in risk assessment 
Mutation research  2010;705(3):172-183.
Gene-environment interactions contribute to complex disease development. The environmental contribution, in particular low-level and prevalent environmental exposures, may constitute much of the risk and contribute substantially to disease. Systematic risk evaluation of the majority of human chemical exposures, has not been conducted and is a goal of regulatory agencies in the U.S. and worldwide. With the recent recognition that toxicological approaches more predictive of effects in humans are required for risk assessment, in vitro human cell line data as well as animal data are being used to identify toxicity mechanisms that can be translated into biomarkers relevant to human exposure studies. In this review, we discuss how data from toxicogenomic studies of exposed human populations can inform risk assessment, by generating biomarkers of exposure, early effect, and/or susceptibility, elucidating mechanisms of action underlying exposure-related disease, and detecting response at low doses. Good experimental design incorporating precise, individual exposure measurements, phenotypic anchors (pre-disease or traditional toxicological markers), and a range of relevant exposure levels, is necessary. Further, toxicogenomic studies need to be designed with sufficient power to detect true effects of the exposure. As more studies are performed and incorporated into databases such as the Comparative Toxicogenomics Database (CTD) and Chemical Effects in Biological Systems (CEBS), data can be mined for classification of newly tested chemicals (hazard identification), and, for investigating the dose-response, inter-relationship among, genes, environment and disease in a systems biology approach (risk characterization).
doi:10.1016/j.mrrev.2010.04.001
PMCID: PMC2928857  PMID: 20382258
12.  Job load and hazard analysis: a method for the analysis of workplace conditions for occupational health care. 
One requirement for successful occupational health care is reliable information on occupational hazards. The aim of this study was to develop a simple, standardised method for workplace investigations for use in occupational health care. The theoretical framework of the method comprises the stress-strain model, the hazard-danger model, and risk behaviour theory. The new method, termed job load and hazard analysis, includes four stages: identification of hazards, their evaluation, conclusions and proposals, and follow up. Different methods are available for hazard identification. The identification starts with a rough analysis of five factors, chemical hazards, physical hazards, physical load, mental stress, and accident risk. Hazards and stress factors are assessed with an ordinal scale. Specialised methods are used if all hazards cannot otherwise be identified. The analytical procedure comprises: detection of hazards through observations and interviews at the workplace and with a questionnaire; assessment of findings as teamwork; and evaluation of the results of these assessments to yield conclusions and proposals made by occupational health care personnel. A data processing system has been developed for data storage and future use. The method has functioned in practice, improving the contents of the occupational health care programme and generating preventive measures. The method offers many new possibilities for controlling occupational hazards and studying relations between working conditions and workers' health.
PMCID: PMC1007554  PMID: 4041383
13.  The Hazard Evaluation System and Information Service: A Physician's Resource in Toxicology and Occupational Medicine 
Western Journal of Medicine  1982;137(6):560-571.
Hazard evaluation is an emerging science. The Hazard Evaluation System and Information Service (HESIS), part of California's program in preventive occupational health, is a resource for clinicians who wish to stay abreast of the relationship between toxicology and occupational health. For example, advances in assays for cancer or reproductive effects in test animals enable us to identify with greater confidence significant cancer or reproductive hazards among the increasing variety of workplace exposures. Occupational experiences with dibromochloropropane (DBCP), Kepone, bis(chloromethyl) ether, benzidine and vinyl chloride demonstrate the shortcomings of relying on human data. The latency period of cancer, limited sensitivity of epidemiologic studies and severity of effects require us to use animal test data to evaluate the potential cancer and reproductive risks of workplace substances. HESIS gives appropriate weight to experimental data in hazard evaluations of chemicals such as ethylene oxide, ethylene dibromide, polychlorinated biphenyls and the glycol ethers. A similar approach is apparent in the California Department of Health Services' recently released Carcinogen Identification Policy.
PMCID: PMC1274235  PMID: 6819719
14.  Lead toxicity: from overt to subclinical to subtle health effects. 
Although the toxicity of lead was recognized centuries ago, concern was restricted to overt symptoms: colic, encephalopathy, anemia, or renal disease. Two major reasons for lack of progress in restricting toxicity were that interest was limited to occupational exposures and there was lack of awareness of specific biochemical or metabolic effects. Identification of subclinical effects has been possible the last 15 or 20 years because of the development of sensitive measures to detect cognitive and behavioral changes that are not apparent clinically and because of methods to measure the reduced activity of heme enzymes. This progress was driven by basic and clinical research that resulted in a better understanding of cellular toxicology. The new awareness prompted the lowering of acceptable occupational exposures, as measured by blood lead from 80 to 40 to 60 micrograms/dL range, and the establishment of maximum recommended exposures in children to a blood lead level of 25 micrograms/dL. Lowering the lead content in gasoline has been accomplished by a nearly 50% decrease in average blood levels of persons in the United States (NHANES II data). Current research implicates lead as a contributing etiologic factor in a number of common diseases affecting large portions of the population such as subtle cognitive and neurological deficits, hypertension, congenital malformations, immunotoxicity, and deficits in growth and development. For each of these disorders there may be multiple etiologic factors; the scientific challenge is to develop sensitive methodology to detect the specific role of lead. Other potential subtle health effects include the influence of small amounts of lead on cell proliferation and lead as a cofactor in carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Images
PMCID: PMC1567746  PMID: 2205487
15.  Toxicological and epidemiological evidence for health risks from inhaled engine emissions. 
Environmental Health Perspectives  1994;102(Suppl 4):165-171.
Information from toxicological and epidemiological studies of the cancer and noncancer health risks from inhaled diesel engine exhaust (DE) and gasoline engine exhaust (GE) was reviewed. The toxicological database is more extensive for DE than for GE. Animal studies have shown that heavy, chronic exposures to both DE and GE can cause lung pathology and associated physiological effects. Inhaled GE has not been shown to be carcinogenic in animals. Chronically inhaled DE at high concentrations is a pulmonary carcinogen in rats, but the response is questionable in mice and negative in Syrian hamsters. The response in rats is probably not attributable to the DE soot-associated organic compounds, as previously assumed, and the usefulness of the rat data for predicting risk in humans is uncertain. Experimental human exposures to DE show that lung inflammatory and other cellular effects can occur after single exposures, and sparse data suggest that occupational exposures might affect respiratory function and symptoms. Epidemiology suggests that heavy occupational exposures to exhaust probably increase the risks for mortality from both lung cancer and noncancer pulmonary disease. The small magnitudes of the increases in these risks make the studies very sensitive to confounding factors and uncertainties of exposure; thus, it may not be possible to resolve exposure-response relationships conclusively by epidemiology. Our present knowledge suggests that heavy occupational exposures to DE and GE are hazardous but does not allow quantitative estimates of risk with a high degree of certainty.
PMCID: PMC1566926  PMID: 7529701
16.  Integrating zebrafish toxicology and nanoscience for safer product development 
The design, manufacture and application of safer products and manufacturing processes have been important goals over the last decade and will advance in the future under the umbrella of "Green Chemistry". In this review, we focus on the burgeoning diversity of new engineered nanomaterials (ENMs) and the prescient need for a nanotoxicology paradigm that quickly identifies potentially hazardous nanochemistries. Advances in predictive toxicological modeling in the developing zebrafish offer the most immediate translation to human hazard that is practically achievable with high throughput approaches. Translation in a vertebrate model that is also a low cost alternative to rodents for hazard prediction has been a desirable but elusive testing paradigm. The utility of zebrafish, if applied early in the ENM discovery pipeline, could greatly enhance efforts toward greener and more efficient nanoscience. Early pipeline detection of human and environmental health impacts will quickly inform decisions in the design and production of safer commercial ENMs.
doi:10.1039/C3GC36806H
PMCID: PMC3680127  PMID: 23772181
17.  Toxicology Testing in Fatally Injured Workers: A Review of Five Years of Iowa FACE Cases 
Toxicology testing of fatally injured workers is not routinely conducted. We completed a case-series study of 2005–2009 occupational fatalities captured by Iowa’s Fatality Assessment and Control Evaluation (FACE) Program. The goals of our research were to: (1) measure the proportion of FACE cases that undergo toxicology testing, and describe the factors associated with being tested, and (2) measure the rate of positive toxicology tests, the substances identified and the demographics and occupations of victims who tested positive. Case documents and toxicology laboratory reports were reviewed. There were 427 occupational deaths from 2005 to 2009. Only 69% underwent toxicology testing. Younger workers had greater odds of being tested. Among occupational groups, workers in farming, fishing and forestry had half the odds of being tested compared to other occupational groups. Of the 280 cases with toxicology tests completed, 22% (n = 61) were found to have positive toxicology testing. Commonly identified drug classes included cannabinoids and alcohols. Based on the small number of positive tests, older victims (65+ years) tested positive more frequently than younger workers. Management, business, science, arts, service and sales/office workers had proportionately more positive toxicology tests (almost 30%) compared with other workers (18–22%). These results identify an area in need of further research efforts and a potential target for injury prevention strategies.
doi:10.3390/ijerph10116154
PMCID: PMC3863892  PMID: 24240727
injury; occupational; fatality; drugs; alcohol
18.  Reproductive toxicity of the industrial solvent 2-ethoxyethanol in rats and interactive effects of ethanol. 
The solvent, 2-ethoxyethanol, induced complete embryomortality in pregnant rats exposed to three times the current Federal permissible exposure limit (PEL). Following exposure to ethoxyethanol at a concentration only one-half the current PEL, the offspring evidenced behavioral and neurochemical deviations from controls. Subsequent studies found that ingestion of ethanol with concomitant inhalation of ethoxyethanol vapors early in pregnancy appeared to reduce the number of both behavioral and neurochemical deviations found for ethoxyethanol. In contrast, the concomitant exposure to ethanol and ethoxyethanol later in gestation potentiated the behavioral and neurochemical effects of ethoxyethanol. This research indicates that the industrial solvent 2-ethoxyethanol presents an occupational reproductive hazard and raises the issue of the importance of an interaction of social habits with occupational exposure to such hazards. The results would suggest that occupational physicians should advise pregnant workers in the chemical industry of the adverse effects of ethanol during pregnancy and of the possible interactions with other chemicals and should encourage them to be especially cautious with ethanol consumption since they may be at greater risk.
PMCID: PMC1568268  PMID: 6499811
19.  Concordance between self-reported substance use and toxicology among HIV-infected and uninfected at risk youth 
Drug and alcohol dependence  2013;134:376-382.
Background
Substance use by youth living with HIV (YLWH) is a concern, given potential interactions with virus-associated immune suppression and adverse effects on risk behaviors, neurocognition, and adherence. Self-report substance use measures provide efficient cost-effective assessments. Analyses describe self-reported substance use among YLWH and examine agreement with toxicology assays.
Methods
Seventy-eight youth age 18–24 years (87% male, 71% African–American) with behaviorally acquired HIV-1 infection and 55 uninfected youth completed the Alcohol, Smoking, and Substance Involvement Screening Test to assess drug use frequency, including tobacco, marijuana, cocaine, and alcohol, over the prior three months. Elisa-based toxicology assays were used to detect 27 substances in plasma. Chi-square tests compared substance use between YLWH and uninfected youth; Kappa statistics compared agreement between self-report and toxicology.
Results
YLWH reported marijuana (49%), tobacco (56%), and alcohol (87%) use, with 20%, 28% and 3% reporting daily use of each substance, respectively; other substance use was uncommon. Uninfected youth reported less tobacco use but otherwise similar substance use. All youth who reported daily use of marijuana or tobacco had positive plasma toxicology results, while concordance decreased with less frequent self-reported use. Among youth reporting no substance use, few tested positive (4% YLWH, 2% uninfected youth for cannabis; 8%YLWH for tobacco).
Conclusions
Youth report high rates of marijuana, tobacco, and alcohol use. Concordance between self-report and toxicology for marijuana and tobacco use, particularly for daily users, supports self-report as a valid indicator of substance use in research studies of youth with or without HIV-1 infection.
doi:10.1016/j.drugalcdep.2013.11.010
PMCID: PMC4006963  PMID: 24309297
HIV; Adolescent; Substance use; Marijuana; Self-report; Toxicology
20.  Occupational Medicine: Opportunities for Family Physicians 
Canadian Family Physician  1989;35:2265-2269.
Occupational medicine has grown recently in sophistication and strength. Occupational physicians with specialty certification focus their attention on toxicology and health hazards in the workplace, compliance with regulatory requirements, and preventive services. These physicians are often employed by organizations. Most occupational health care will continue to be provided by family physicians, who may also be the physicians closest to the workers and their families. There are many opportunities for family physicians to develop their skills in occupational health care and to incorporate occupational medicine into their practices.
PMCID: PMC2280288  PMID: 21248919
family medicine; medical education; occupational medicine; specialist consultation
21.  Investigation of an acute chemical incident: exposure to fluorinated hydrocarbons 
OBJECTIVES—To assess whether attendance at the site after an incident in a sewer was associated with symptoms in emergency personnel and whether the prevalence of symptoms was associated with estimated levels of exposure to any chemical hazard.
METHODS—Symptoms experienced by people attending an incident involving two dead sewer workers suggested the presence of a chemical hazard, before environmental sampling confirmed any toxic agent. Self reported symptoms, estimated exposures, and biomarkers of exposure for likely agents from all 254 people who attended the incident and a referent occupational group matching the 83 emergency personnel who went to the Accident and Emergency department (A and E) in the first 48 hours were recorded. The prevalence of symptoms and concentrations of creatine phosphokinase in serum of the 83 early patients at A and E were compared with their referent occupational group. In all workers who attended the incident, the trends in symptom prevalences and concentrations of creatine phosphokinase in serum were examined by distance from the site and predefined exposure category.
RESULTS—Among all workers who attended the incident, symptoms of shortness of breath and sore throat were significantly associated with indirect estimates of exposure but not associated with concentrations of creatine phosphokinase. Freon was detected in two blood samples. The early patients at A and E reported more symptoms than their matched reference group and their median concentrations of creatine phosphokinase were higher.
CONCLUSIONS—The association between symptoms and concentrations of creatine phosphokinase with attendance at the site indicated the presence of a continuing hazard at the site and led to extra precautions being taken. Comparison values from the referent occupational group prevented unnecessary medical follow up.


Keywords: pollution; chemical; population
doi:10.1136/oem.57.9.577
PMCID: PMC1740011  PMID: 10935937
22.  Environmental Isocyanate-Induced Asthma: Morphologic and Pathogenetic Aspects of an Increasing Occupational Disease 
Occupational diseases affect more and more people every year. According to the International Labour Organization (ILO), in 2000 an estimated amount of at least 160 million people became ill as a result of occupational-related hazards or injuries. Globally, occupational deaths, diseases and injuries account for an estimated loss of 4% of the Gross Domestic Product. Important substances that are related to occupational diseases are isocyanates and their products. These substances, which are used in a lot of different industrial processes, are not only toxic and irritant, but also allergenic. Although the exposure to higher concentrations could be monitored and restricted by technical means, very low concentrations are difficult to monitor and may, over time, lead to allergic reactions in some workers, ending in an occupational disease. In order to prevent the people from sickening, the mechanisms underlying the disease, by patho-physiological and genetical means, have to be known and understood so that high risk groups and early signs in the development of an allergic reaction could be detected before the exposure to isocyanates leads to an occupational disease. Therefore, this paper reviews the so far known facts concerning the patho-physiologic appearance and mechanisms of isocyanate-associated toxic reactions and possible genetic involvement that might trigger the allergic reactions.
doi:10.3390/ijerph8093672
PMCID: PMC3194110  PMID: 22016709
occupational disease; isocyanate; occupational asthma; pathological findings; clinical findings; genetic predisposition
23.  Mutagenicity of an aged gasworks soil during bioslurry treatment 
This study investigated changes in the mutagenic activity of organic fractions from soil contaminated with polycyclic aromatic hydrocarbons (PAHs) during pilot-scale bioslurry remediation. Slurry samples were previously analyzed for changes in PAH and polycyclic aromatic compound content, and this study examined the correspondence between the chemical and toxicological metrics. Nonpolar neutral and semipolar aromatic fractions of samples obtained on days 0, 3, 7, 24, and 29 of treatment were assayed for mutagenicity using the Salmonella mutation assay. Most samples elicited a significant positive response on Salmonella strains TA98, YG1041, and YG1042 with and without S9 metabolic activation; however, TA100 failed to detect mutagenicity in any sample. Changes in the mutagenic activity of the fractions across treatment time and metabolic activation conditions suggests a pattern of formation and transformation of mutagenic compounds that may include a wide range of PAH derivatives such as aromatic amines, oxygenated PAHs, and S-heterocyclic compounds. The prior chemical analyses documented the formation of oxygenated PAHs during the treatment (e.g., 4-oxapyrene-5-one), and the mutagenicity analyses showed high corresponding activity in the semipolar fraction with and without metabolic activation. However, it could not be verified that these specific compounds were the underlying cause of the observed changes in mutagenic activity. The results highlight the need for concurrent chemical and toxicological profiling of contaminated sites undergoing remediation to ensure elimination of priority contaminants as well as a reduction in toxicological hazard. Moreover, the results imply that remediation efficacy and utility be evaluated using both chemical and toxicological metrics. Environ. Mol. Mutagen. 2009. © 2009 Wiley-Liss, Inc.
doi:10.1002/em.20473
PMCID: PMC2909460  PMID: 19274766
bioremediation; polycyclic aromatic hydrocarbons; contaminated soil; mutagenicity
24.  A proposal to improve clarity and communication in the EU Classification process for chemicals for carcinogenicity and reproductive and developmental toxicity 
Journal of Applied Toxicology  2014;34(10):1068-1072.
There is an issue in the EU classification of substances for carcinogenicity and for reproductive or developmental toxicity which has brought difficulties to those involved in the process. The issue lies in the inability of the classification system to distinguish between carcinogens and reproductive toxicants with different levels of concern. This has its origins in the early years of toxicology when it was thought that a relatively small number of chemicals would be either carcinogens or reproductive toxicants, but this has turned out not to be the case. This can cause problems in communicating to the users of chemicals, including the public, the nature of the hazard presented by chemicals. Processes have been developed within the classification system for setting specific concentration limits which assess the degree of hazard for carcinogens and reproductive toxicants as high, medium or low. However these categories are not otherwise used in classification. It is proposed that their wider use would bring the advantages of transparency, clarity of communication, certainty of the process and would allow chemicals with a high degree of hazard to be identified and managed in an appropriate way. Copyright © 2014. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.
The inability of the EU classification system to distinguish between carcinogens and reproductive toxicants with different levels of concern can cause problems in communicating to the users of chemicals the nature of the hazard presented by chemicals. Processes have been developed by the EU for assessing the degree of hazard for carcinogens and reproductive toxicants as high, medium or low. Using them more widely would bring the advantage of transparency, clarity of communication and certainty of the process.
doi:10.1002/jat.3045
PMCID: PMC4255787  PMID: 25059745
carcinogenicity; reproductive toxicity; classification; degree of hazard; hazard characterization
25.  Health Behaviours, Socioeconomic Status, and Mortality: Further Analyses of the British Whitehall II and the French GAZEL Prospective Cohorts 
PLoS Medicine  2011;8(2):e1000419.
Further analysis of data from two prospective cohorts reveals differences in the extent to which health behaviors attenuate associations between socioeconomic position and mortality outcomes.
Background
Differences in morbidity and mortality between socioeconomic groups constitute one of the most consistent findings of epidemiologic research. However, research on social inequalities in health has yet to provide a comprehensive understanding of the mechanisms underlying this association. In recent analysis, we showed health behaviours, assessed longitudinally over the follow-up, to explain a major proportion of the association of socioeconomic status (SES) with mortality in the British Whitehall II study. However, whether health behaviours are equally important mediators of the SES-mortality association in different cultural settings remains unknown. In the present paper, we examine this issue in Whitehall II and another prospective European cohort, the French GAZEL study.
Methods and Findings
We included 9,771 participants from the Whitehall II study and 17,760 from the GAZEL study. Over the follow-up (mean 19.5 y in Whitehall II and 16.5 y in GAZEL), health behaviours (smoking, alcohol consumption, diet, and physical activity), were assessed longitudinally. Occupation (in the main analysis), education, and income (supplementary analysis) were the markers of SES. The socioeconomic gradient in smoking was greater (p<0.001) in Whitehall II (odds ratio [OR]  = 3.68, 95% confidence interval [CI] 3.11–4.36) than in GAZEL (OR  = 1.33, 95% CI 1.18–1.49); this was also true for unhealthy diet (OR  = 7.42, 95% CI 5.19–10.60 in Whitehall II and OR  = 1.31, 95% CI 1.15–1.49 in GAZEL, p<0.001). Socioeconomic differences in mortality were similar in the two cohorts, a hazard ratio of 1.62 (95% CI 1.28–2.05) in Whitehall II and 1.94 in GAZEL (95% CI 1.58–2.39) for lowest versus highest occupational position. Health behaviours attenuated the association of SES with mortality by 75% (95% CI 44%–149%) in Whitehall II but only by 19% (95% CI 13%–29%) in GAZEL. Analysis using education and income yielded similar results.
Conclusions
Health behaviours were strong predictors of mortality in both cohorts but their association with SES was remarkably different. Thus, health behaviours are likely to be major contributors of socioeconomic differences in health only in contexts with a marked social characterisation of health behaviours.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The influence of the socioeconomic environment on the health of individuals and populations is well known, giving rise to the so-called social determinants of health. The social determinants of health are the conditions in which people are born, grow, live, work, and age, including the health system. These circumstances are shaped by the distribution of money, power, and resources at global, national, and local levels, which are themselves influenced by policy choices. The social determinants of health are mostly responsible for health inequities—the unfair and avoidable differences in health status seen within and between countries. In addition, health-damaging behaviors are often strongly socially patterned. For example, material constraints, lack of knowledge, and limited opportunities to follow health promoting messages often act as barriers that prevent those from lower socioeconomic groups to adopt a healthy lifestyle. Yet the extent to which health behaviors explain social inequalities in health remains unclear and can range from 12% to 72% according to some studies.
Why Was This Study Done?
In a recently published paper using data from the British Whitehall II cohort, the researchers showed that longitudinal assessment of health behaviors accounted for socioeconomic differences in mortality better than a single baseline assessment as used in most previous studies. (The Whitehall II study started in 1985 to examine the socioeconomic gradient in health among 10,308 London-based civil servants [6,895 men and 3,413 women] aged 35–55).
However, it is not clear whether health behaviors are equally important mediators of the socioeconomic-health association in different cultural settings. In this study, the researchers examine this issue by comparing their recent findings of the Whitehall II study with another European cohort, the French GAZEL study. (The GAZEL study started in 1989 among employees of the French national gas and electricity company totaling 20,625 employees [15,011 men and 5,614 women], aged 35–50.) The Whitehall II study and the GAZEL study have comparable designs in the way both assess socioeconomic status, health behaviors, and mortality and have a similar age range and follow-up period.
What Did the Researchers Do and Find?
The researchers included 9,771 participants from the Whitehall II study and 17,760 from the GAZEL study—mean follow up for Whitehall II was 19.5 years and for GAZEL was 16.5 years. The researchers used occupation as the main marker of socioeconomic status, and education and income as supplementary markers of socioeconomic status. Apart from a few exceptions, the researchers analyzed each cohort separately and used statistical techniques to calculate: the mortality rates per 1000 person-years for each socioeconomic group; the age- and sex-adjusted prevalence rates of smoking, heavy alcohol consumption, unhealthy diet, and physical inactivity, at the first and the last follow-up of the study for each socioeconomic group; and the differences in health behaviors prevalence between lowest and highest occupational position. Then the researchers used a statistical model to deduce the contribution of all health behaviors.
The researchers found that the socioeconomic gradient in smoking, unhealthy diet, and physical inactivity was greater in Whitehall II than in GAZEL. Socioeconomic differences in mortality were similar in the two cohorts, a hazard ratio of 1.62 in Whitehall II and 1.94 in GAZEL for lowest versus highest occupational position. Health behaviors weakened the association between socioeconomic status and mortality by 75% in Whitehall II but only by 19% in GAZEL. The supplementary analysis the researchers conducted using education and income as socioeconomic markers gave similar results.
What Do These Findings Mean?
These results suggest that the social patterning of unhealthy behaviors differs between countries. Although in both cohorts socioeconomic status and health behaviors were strong predictors of mortality, major differences in the social patterning of unhealthy behaviors in the two cohorts meant that the causal chains leading from socioeconomic status to health behaviors to mortality were different. Therefore it may be that health behaviors are likely to only be major contributors of socioeconomic differences in health in contexts with a marked social characterization of those behaviors. In order to identify the common and unique determinants of social inequalities in health in different populations, there needs to be further comparative research on the relative importance of different pathways linking socioeconomic status to health.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000419.
WHO provides information on social determinants of health
University College London provides information on the Whitehall study
The GAZEL study is available in an online open access format
doi:10.1371/journal.pmed.1000419
PMCID: PMC3043001  PMID: 21364974

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