Hazards from chemicals: scientific questions and conflicts of interest.

All substances are toxic when the dose is large enough. In order to regulate the use of chemicals, we need to measure the level at which toxic effects are found. Epidemiological evidence suggests that present levels of chemical use do not lead to widespread harmful contamination of the human environment. For chemicals, most of the problems of toxicity are found in the workplace, while the population at large gets most of its toxic effects from voluntary exposure to substances such as tobacco smoke and ethanol. The prevention and control of toxic effects depends on a series of steps. This begins with measurement of toxicity in model systems, such as laboratory animals, and the estimation of the likely exposure of workers or consumers. Reliable extrapolation of information gathered from animals to the diverse and biochemically differing human population depends on understanding mechanisms of toxic effects. The toxic effect and mechanisms of action of substances such as carbon tetrachloride or paracetamol have been extensively investigated, and our ability to predict toxicity or develop antidotes to poisoning has had some success, but epidemiology is still an essential part of assessment of toxic effects of new chemicals. The example of phenobarbitone shows how animal experiments may well lead to conclusions which do not apply to man. After measurement of toxicity and assessment of likely hazards in use comes the final evaluation of the use of a chemical. This depends not only on its toxicity, but also on its usefulness. The direct effects on health may be small in comparison with the indirect advantageous effects which a useful substance such as vinyl chloride may bring. The assessment of risks and benefits of new chemicals can be partly removed from a political style of discourse, but the evaluation of the relative weight to be attached to these risks and benefits is inescapably political. The scientific contribution must be to allow the debate to take place in the light of maximum clarity of information about the consequences of use of chemicals.     

Regional medico-dosimetric register (RMDR) is a model for evaluation of long-term "low" dose ionizing radiation effects on Siberian group of chemical enterprises main production personnel

Medico-dosimetric register is an optimal model of epidemiological studies on evaluation of ionizing radiation effects. Regional medico-dosimetric register (RMDR) is a system of interrelating information blocks including data on Siberian Group of Chemical Enterprises (SGCE) personnel. At present SGCE personnel and Seversk residents RMDR database includes information on 138496 persons, 65538 of which are SGCE workers. SGCE personnel and Seversk residents RMDR is a scientific base for researches with the aim of evaluating long-term ionizing radiation effects in a "low" dose range. Information on mortality and morbidity rate as well as "thematic" registers of the main diseases potentiates in evaluating the spectrum of somatic stochastic effects and radiogenic risks in SGCE workers and Seversk residents as well as their offsprings. A practical significance of RMDR database is the formation of the main diseases "risk" groups depending on definite risk factors in certain groups that provides targeted diagnostic and preventive therapy both among high-dose establishments' workers and residents living near-by.     

Health risk assessment of occupational exposure to styrene depending on the type of industry: Data from the Workplace Environmental Monitoring Program in Korea

Data from the Workplace Environmental Monitoring Program was used to evaluate the concentrations and risk of occupational exposure to styrene in different industries to identify which industries should be prioritized for styrene exposure management. Risk assessments were conducted for the five industries with several workplaces that mostly use styrene: motor vehicle and motorcycle maintenance and repair services, other chemical product manufacturing, ship and boat building, basic chemical manufacturing, and plastic products manufacturing. The highest central tendency exposure was found in the plastic products manufacturing industry (10.14 mg/m³). In addition, the hazard quotient (HQ) for central tendency exposure exceeded 1 only in the plastic products manufacturing industry. Almost two-thirds (62.2%) of workplaces in the plastic products manufacturing industry have an HQ exceeding 1. We conclude that workers in the plastic products manufacturing industry are at the highest risk for styrene exposure, and those in motor vehicle and motorcycle maintenance and repair service and basic chemical manufacturing are at the lowest risk. These results show that styrene exposure could be most effectively managed by prioritizing control measures in the plastic products manufacturing industry.     

A follow-up study of women in the synthetic rubber industry: study methods

BACKGROUND: Concerns about the possible toxic effects of workplace exposures in the synthetic rubber industry have centered on 1,3-butadiene (BD), styrene and dimethyldithiocarbamate (DMDTC). Our previous mortality studies of over 17,000 male synthetic rubber workers found an excess of leukemia that may be due to BD or BD plus other chemicals. Experimental studies have shown that BD produces mammary tumors in female mice and rats and ovarian tumors in female mice. AIM: This paper presents the methods of a follow-up study that evaluates the mortality experience of women employed in the North American synthetic rubber industry. METHODS: Women employed for at least 1 day at any of eight North American styrene-butadiene rubber plants were followed up from 1943 to 2002. Identifying and work history information were obtained from personnel records. Estimated quantitative exposure to BD, styrene and DMDTC, developed for our previous study of men, were used in this study. External analyses use the standardized mortality ratios (SMRs) to compare the cohort's cause-specific mortality rates to the rates of the female general population of the states or the province where the plants are located. Internal analyses use the Poisson regression and Cox proportional hazards models to examine specific cancer mortality rates in relation to BD, styrene and DMDTC exposure, by comparing an exposed cohort subgroup with the rate of unexposed cohort members.     

Risk factors occurring in various types of acute leukemia

The present investigations demonstrate that as far as the genesis of non-lymphatic leukemias is concerned environmental factors may be assumed as an aetiological factor to an increasing extent. Medicaments, particularly cytostatics, exogenous noxious occupational agents and infectious-inflammatory diseases might be significant for developing ANLL, whereas virus infection, immunizations, and acclimatization to specific conditions of climate may be rather attributed as risk factors for ALL. A tendency to deviations from the blood picture ( lymphomonocytosis , leukocytopenia, toxic granulation of neutrophilic granulocytes) can be increasingly observed in workers engaged in chemical industry, with these changes, being still reversible. A permanent effect of exogenous toxic agents, however, will produce a serious damage of the bone-marrow. Further investigations are provided for elucidating the function of different haemopoietic cell systems, particularly the immune status, in workers of those enterprises where an exposure to noxious substances can be found.     

Adverse health effects in workers exposed to trace/toxic metals at workplace

Widespread use of metals in industrial activities has enhanced the occupational exposure to toxic metals as well as the health risks of metal hazards to humans. Elemental analysis in human tissues is the most common application of biological monitoring for screening, diagnosis and assessment of such exposures and risk. Among various biopsy materials, blood, hair, nail, teeth and body fluids may be used as bioindicators for this purpose. The present paper deals with the determination of Pb, Cr, Ni, Mn, Fe, Cu and Zn elemental concentration in workers exposed to these metals at workplace by atomic absorption spectrophotometry, with adequate quality control measures using hair as biopsy material. The study group includes the male workers such as welders, foundry man, fitter, hammer man, machine man, cupola man etc., besides office workers of locomotive workshop in Ajmer and surrounding areas exposed to different metals. Age and sex matched controls of persons working in the same area of work in offices etc. and not exposed to metal pollution were selected for valid comparison. It is proposed to validate the use of hair as a biological marker for assessing metal body burden of workers. In our study significant correlations have been found between skin disease and Cr, Mn, Fe, Cu; chest pain and Pb; hypertension and Cu, Mn; mental stress and Mn, Ni, Cu, Zn; liver problem and Ni; indigestion and Cr; Ni, diabetes and Cr, Mn, Ni; tuberculosis and Zn; breathing trouble and Cr, Mn, Fe, Ni, Zn. The advantages of choosing hair as a biopsy material are also given.     

Toxicity of thiols and disulphides: Involvement of free-radical species

Sulphur is essential to life, and thiols and disulphides play essential roles in cellular biochemistry. Such compounds are also widely distributed in the food of man and his domestic animals, and they are extensively used in industry. However, many thiols and disulphides have been shown to be toxic. Aliphatic, aromatic, and heterocyclic compounds of this type are haemolytic agents in animals while aminothiols have been shown to induce many cytotoxic effects in vitro and the epidithiodioxopiperazine mycotoxin, sporidesmin, is a potent hepatotoxic agent. Structure-activity relationships among these compounds and factors which modulate their harmful effects are consistent with a toxic mechanism involving redox cycling between the thiol and the corresponding disulphide. Thiyl radicals and "active oxygen" species are formed in this process, and it is suggested that these substances are responsible for initiating the tissue damage provoked by thiols and disulphides.     

Overview of Toxicity Data and Risk Assessment Methods for Evaluating the Chemical Effects of Depleted Uranium Compounds

In the United States, depleted uranium is handled or used in several chemical forms by both governmental agencies and private industry (primarily companies producing and machining depleted uranium metal for military applications). Human exposure can occur as a result of handling these compounds, routine low-level effluent releases to the environment from processing facilities, or materials being accidentally released from storage locations or during processing or transportation. Exposure to uranium can result in both chemical and radiological toxicity, but in most instances chemical toxicity is of greater concern. This article discusses the chemical toxic effects from human exposure to depleted uranium compounds that are likely to be handled during the long-term management and use of depleted uranium hexafluoride (UF₆) inventories in the United States. It also reviews representative publications in the toxicological literature to establish appropriate reference values for risk assessments. Methods are described for evaluating chemical toxicity caused by chronic low-level exposure and acute exposure. Example risk evaluations are provided for illustration. Preliminary results indicate that chemical effects of chronic exposure to uranium compounds under normal operating conditions would be negligibly small. Results also show that acute exposures under certain accident conditions could cause adverse chemical effects among the populations exposed.     

Results of cytogenetic testing of workers exposed to ethylene oxide

The present work was undertaken to test cytogenetically workers exposed to Ethylene oxide (EO) aiming at detecting possible adverse effects of this agent to man. In the period 1983-1984, female workers of the Laboratory of Toxicology and the Production laboratory of ethylene oxide production in a chemical plant, and female workers in a sterilization centers in a medical facilities, were repeatedly examined. In 1984, also workers in ethylene oxide production in a chemical plant were tested. For each exposed group a control group was simultaneously examined, using cytogenetic analysis of peripheral blood lymphocytes. General examination of the health condition of exposed workers were organized in the framework of preventive examinations. The exposure level to ethylene oxide in the working environment was simultaneously monitored. The results have revealed an increase in chromosomal aberrations in lymphocytes of persons exposed professionally to EO at the given exposure levels. Smoking was associated with increased frequency of chromosomal aberrations in exposed workers; the difference as compared to non-smokers was however insignificant. By contrast, difference in chromosomal aberration frequency between smokers and non-smokers was significant in the control group.     

Evaluation of genotoxicity in a group of workers from a petroleum refinery aromatics plant

Petroleum refinery workers are potentially exposed to a wide range of petroleum-derived hydrocarbons and chemical substances used in the manufacturing of petroleum derivatives. Benzene, toluene and xylene (BTX) are produced by distillation in the aromatics units and used as raw materials for petrol and petrochemical products. The aim of this study was to evaluate the genotoxic effects of occupational exposure to BTX in a petroleum refinery in the North of Portugal. The exposed group consisted of 48 workers from the aromatics plant and the control group consisted of 30 persons matched for various confounding factors. Chromosome aberrations (CA), micronuclei (MN), and DNA damage (evaluated by means of the comet assay) were measured in peripheral blood leukocytes. t,t-Muconic acid (t,t-MA), hippuric acid (HA) and methylhippuric acid (MHA) concentrations were measured in urine samples collected at the end of the workshift. The results suggest that occupational exposure to toluene and xylene is very low. A statistically significant increase in t,t-MA excretion was found in the exposed group although t,t-MA levels were found to be lower than the biological exposure index (BEI). Significant increases were found for CA, MN and comet tail length (TL) in the exposed group (p<0.05). No association was found between tobacco smoking and the effect biomarkers analysed. A positive association was found between CA and MN with age in the control group (p<0.05).     

Respiratory Health – Exposure Measurements and Modeling in the Fragrance and Flavour Industry

Although the flavor and fragrance industry is about 150 years old, the use of synthetic materials started more than 100 years ago, and the awareness of the respiratory hazard presented by some flavoring substances emerged only recently. In 2001, the US National Institute of Occupational Safety and Health (NIOSH) identified for the first time inhalation exposure to flavoring substances in the workplace as a possible occupational hazard. As a consequence, manufacturers must comply with a variety of workplace safety requirements, and management has to ensure the improvement of health and safety of the employees exposed to hazardous volatile organic compounds. In this sensitive context, MANE opened its facilities to an intensive measuring campaign with the objective to better estimate the real level of hazardous respiratory exposure of workers. In this study, exposure to 27 hazardous volatile substances were measured during several types of handling operations (weighing-mixing, packaging, reconditioning-transferring), 430 measurement results were generated, and were exploited to propose an improved model derived from the well-known ECETOC-TRA model. The quantification of volatile substances in the working atmosphere involved three main steps: adsorption of the chemicals on a solid support, thermal desorption, followed by analysis by gas chromatography-mass spectrometry. Our approach was to examine experimental measures done in various manufacturing workplaces and to define correction factors to reflect more accurately working conditions and habits. Four correction factors were adjusted in the ECETOC-TRA to integrate important exposure variation factors: exposure duration, percentage of the substance in the composition, presence of collective protective equipment and wearing of personal protective equipment. Verification of the validity of the model is based on the comparison of the values obtained after adaptation of the ECETOC-TRA model, according to various exposure scenarios, with the experimental values measured under real conditions. After examination of the predicted results, 98% of the values obtained with the proposed new model were above the experimental values measured in real conditions. This must be compared with the results of the classical ECETOC-TRA system, which generates only 37% of overestimated values. As the values generated by the new model intended to help decision-makers of the industry to implement adapted protective action and information, and considering the high variability of the working environments, it was of the utmost importance to us not to underestimate the exposure level. The proposed correction factors have been designed to achieve this goal. We wish to propose the present method as an improved monitoring tool to improve respiratory health and safety in the flavor and fragrance manufacturing facilities.     

Analysis of chromosomal aberrations in men occupationally exposed to cement dust

Cement industry is considered as a major pollution problem on account of dust and particulate matter emitted at various steps of cement manufacture. Cement dust consists of many toxic constituents. The workers who are employed in cement industries are exposed to cement dust for long periods. Therefore, it is mandatory to evaluate the mutagenic effects of occupational exposure to cement dust in such workers. In the present study, we analyzed the samples of 124 male workers including 59 smokers and 65 non-smokers who were employed in cement industry for a period of 1–17 years. For comparison, 106 controls (including 47 smokers and 59 non-smokers) of the same age group and socio-economic status were also studied. Controls had no exposure to cement dust or any known physical or chemical agent. A significant increase in the incidence of chromosomal aberrations was observed in the exposed group when compared to the control group. The results were analyzed separately for non-smokers and smokers. The chromosomal damage was more pronounced in the smokers when compared with the non-smokers both in control and exposed groups. A significant increase in the frequency of chromosomal aberrations was also observed with increase in age in both control and exposed subjects.     

Analysis of chromosomal aberrations in men occupationally exposed to cement dust

Cement industry is considered as a major pollution problem on account of dust and particulate matter emitted at various steps of cement manufacture. Cement dust consists of many toxic constituents. The workers who are employed in cement industries are exposed to cement dust for long periods. Therefore, it is mandatory to evaluate the mutagenic effects of occupational exposure to cement dust in such workers. In the present study, we analyzed the samples of 124 male workers including 59 smokers and 65 non-smokers who were employed in cement industry for a period of 1-17 years. For comparison, 106 controls (including 47 smokers and 59 non-smokers) of the same age group and socio-economic status were also studied. Controls had no exposure to cement dust or any known physical or chemical agent. A significant increase in the incidence of chromosomal aberrations was observed in the exposed group when compared to the control group. The results were analyzed separately for non-smokers and smokers. The chromosomal damage was more pronounced in the smokers when compared with the non-smokers both in control and exposed groups. A significant increase in the frequency of chromosomal aberrations was also observed with increase in age in both control and exposed subjects.     

Molecular Biomarkers and Epidemiologic Risk Assessment

The use of molecular biomarkers in epidemiologic studies has been advancedas a way to improve risk assessments for occupational and environmental exposuresto toxic agents. We have used the detection of two cancer-related, molecular biomarkers of vinyl chloride exposure (mutant ras-p21 and mutant p53) to examine workers with equivalent cumulative exposures that would be above or below the current permissible workplace exposure limit for vinyl chloride for differences in the presence of these biomarkers. Workers with cumulative exposures above the current permissible exposure limit (equivalent of > 40 ppm-years) have a statistically significantly increased occurrence of both biomarkers in comparison to unexposed controls (p < 10^?3). Although workers with cumulative exposures of < 10 ppm-years, i.e., well below the current limit, do not have a statistically significantly increased occurrence of these biomarkers (p > 0.05), workers with cumulative exposures of 10 to 40 ppm-years, i.e., still below the current limit, are found to have a statistically significant increase (p < 0.05). This suggests that the current exposure limit may not be adequately protective and illustrates the potential utility of molecular biomarkers in the refinement of risk assessments for toxic exposures.     

Research needs to improve risk assessment of fiber toxicity

Risk characterization of exposure to toxic compounds requires information on the intrinsic toxic properties, including toxic mechanism and toxicokinetics, on dose response at the most critical targets for identification of the NOEL or for extrapolation from high to low dose, and on human exposure. Abundant information is available on the intrinsic properties of MMMF, on the three D's (dose, dimension, durability) and on the toxic mechanisms. However, only a few of these studies provide information on the dose response of the effects or of the mechanisms investigated. Moreover, in many cases single high doses exceeding the MTD have been applied and are difficult to interpret for lower exposure scenarios. Risk characterization is further hampered by the still open question whether MMMF are directly genotoxic or induce secondary genotoxicity via inflammation. Finally, there is disagreement about the relevance of animal studies on MMMF for humans and thus about the most rational extrapolation of the dose response of toxic effects observed in animals to man. These deficits are briefly described and discussed from a toxicological point of view.     

Quantitative biomechanical workplace exposure measures: Distribution centers

Physical work exposure characteristics assessed in most previous epidemiologic studies have been described mostly in gross categorical terms (e.g. heavy work, lifting and forceful movements, etc.) and have resulted in relatively moderate associations with low back pain risk. We hypothesized that it was necessary to characterize work demands in a much more quantitative fashion so that the precise biomechanically meaningful measures of exposure were available for risk analysis. In this study, we used sophisticated instrumentation to continuously document 390 physical exposures during lifting (in four types of distribution centers) throughout work. This study profiles these exposures and shows how these exposures vary as a function of the type of distribution center and compares the exposures to (previously documented) manufacturing exposures. Static load and load moment measures were found to greatly under-represent true (dynamic) load and load moment exposures to workers. Lift durations averaged 11–12% of the cycle time in distribution environments. This study indicates that distribution workers are commonly exposed to greater extreme loads and move much more rapidly than manufacturing employees. The information provided here can serve as a basis for low back pain risk assessments.     

Characteristics of the cohort of workers at the Mayak nuclear complex.

At Branch No. 1 of the Russian State Research Center "Biophysics Institute", a registry has been created of workers at the "Mayak" Production Association, the first nuclear complex in Russia. This registry includes 18,830 persons hired at Mayak's nuclear reactors and radiochemical and plutonium production plant between 1948 and 1972. Twenty-five percent of these workers are women. As of December 31, 1994, the vital status is known for approximately 90% of the cohort members. A total of 5,118 persons have died. The cause for 97% of total deaths has been ascertained. The cohort members were exposed to both external gamma radiation and internal radiation from incorporated plutonium. The plutonium body burden has been measured in 30% of the cohort members with potential for plutonium exposure. External gamma-ray doses were in the range from tenths of milligrays to about 10 Gy, and plutonium body burdens were up to about 260 kBq. In view of the nature of the Mayak worker cohort, it has the potential to provide reasonably precise, quantitative estimates of the long-term health effects associated with chronic low-dose-rate exposure to external gamma radiation as well as internal radiation from plutonium. However, a number of issues must be addressed before credible risk estimates can be obtained from this cohort. These issues include the development of an appropriate internal comparison group and/or external rates and separating of the effects of internal and external exposures on risk estimates.     

Nickel: a review of its occupational and environmental toxicology

Nickel and nickel compounds belong to the classic noxious agents encountered in industry, but is also known to affect non-occupationally exposed individuals, especially those handling stainless-steel and nickel plated articles of everyday use. For plants and some vertebrates, specifically for mammals, nickel is indispensable as one of the essential trace elements. The most important health problems due to exposure to nickel and nickel compounds are allergic dermatitis (nickel itch) and increased incidence of cancers of the lungs and nasal mucosa encountered among the workers after a long-term over-exposure to nickel. In this respect the most hazardous nickel compounds appear to be nickel sulfide and nickel oxide. The monitoring of nickel exposure levels can be based on blood serum and urine analyses, but also on nickel determinations in hair which have proved promising even in groups of non-occupationally exposed individuals. Nickel carbonyl is the most toxic of all of the nickel compounds encountered, but because of its relatively short half-life it does not seem to represent any actual biohazard from the standpoint of environmental pollution. To prevent incidence of malignancies it is recommended to include in the routine plan of the preventive medical examinations also the cytologic analysis supplemented, in the case of cytologic positivity, with the bioptic examination for epithelial dysplasia. A systematic medical surveillance of workers with known long-term exposure to nickel is, of course, essential. At present, a major attention is centered on biochemical interactions of nickel with copper, cadmium, iron, iodine and particularly with manganese known to significantly reduce the experimental carcinogenicity of nickel and nickel compounds.     

Mutagenicity, carcinogenicity, and teratogenicity of acrylonitrile.

Acrylonitrile (AN) is an important intermediary for the synthesis of a variety of organic products, such as artificial fibres, household articles and resins. Although acute effects are the primary concern for an exposure to AN, potential genotoxic, carcinogenic and teratogenic risks of AN have to be taken seriously in view of the large number of workers employed in such industries and the world-wide population using products containing and possibly liberating AN. An understanding of the effect of acrylonitrile must be based on a characterization of its metabolism as well as of the resulting products and their genotoxic properties. Tests for mutagenicity in bacteria have in general been positive, those in plants and on unscheduled DNA synthesis doubtful, and those on chromosome aberrations in vivo negative. Wherever positive results had been obtained, metabolic activation of AN appeared to be a prerequisite. The extent to which such mutagenic effects are significant in man depends, however, also on the conditions of exposure. It appears from the limited data that the ultimate mutagenic factor(s), such as 2-cyanoethylene oxide, may have little opportunity to act under conditions where people are exposed because it is formed only in small amounts and is rapidly degraded. The carcinogenic action of AN has been evaluated by various agencies and ranged from 'reasonably be anticipated to be a human carcinogen' to 'cannot be excluded', the most recent evaluation being 'possibly carcinogenic to humans'. Animal data that confirm the carcinogenic potential of AN have certain limitations with respect to the choice of species, type of tumors and length of follow up. Epidemiological studies which sometimes, but not always, yielded positive results, encounter the usual difficulties of confounding factors in chemical industries. Exposure of workers to AN should continue to be carefully monitored, but AN would not have to be considered a cancer risk to the population provided limitations on releases from consumer products and guidelines on AN in water and air are enforced. AN is teratogenic in laboratory animals (rat, hamster) at high doses when foetal/embryonic (and maternal) toxicity already is manifest. Pregnant workers should not be exposed to AN. In view of the small concentrations generally encountered outside plants, women not professionally exposed would appear not to be at risk of teratogenic effects due to AN. Future research should concentrate on the elucidation of the different degradation pathways in man and on epidemiological studies in workers including pregnant women, assessing also, if possible, individual exposure by bio-monitoring.     

Bystander effects, adaptive response and genomic instability induced by prenatal irradiation

The developing human embryo and fetus undergo very radiosensitive stages during the prenatal development. It is likely that the induction of low dose related effects such as bystander effects, the adaptive response, and genomic instability would have profound effects on embryonic and fetal development. In this paper, I review what has been reported on the induction of these three phenomena in exposed embryos and fetuses. All three phenomena have been shown to occur in murine embryonic or fetal cells and structures, although the induction of an adaptive response (and also likely the induction of bystander effects) are limited in terms of when during development they can be induced and the dose or dose-rate used to treat animals in utero. In contrast, genomic instability can be induced throughout development, and the effects of radiation exposure on genome instability can be observed for long times after irradiation including through pre- and postnatal development and into the next generation of mice. There are clearly strain-specific differences in the induction of these phenomena and all three can lead to long-term detrimental effects. This is true for the adaptive response as well. While induction of an adaptive response can make fetuses more resistant to some gross developmental defects induced by a subsequent high dose challenge with ionizing radiation, the long-term effects of this low dose exposure are detrimental. The negative effects of all three phenomena reflect the complexity of fetal development, a process where even small changes in the timing of gene expression or suppression can have dramatic effects on the pattern of biological events and the subsequent development of the mammalian organism.