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Background This is the first published assessment on agricultural pesticide use in Iran with the aim to identify pesticide products with a potential of causing acute or chronic hazard to human health. It also establishes a baseline for future comparisons and for trend assessments. Methods The amounts of imported technical materials for formulation by local manufacturers as well as imported final product formulations were extracted from the registration data of the Plant Protection Organization of Iran in 2012–2014. The hazard indicators used were acute oral toxicity and chronic toxicity. For the latter, carcinogenicity, mutagenicity, and adverse effects on reproduction or development (CMR toxicity), and low Acceptable Daily Intake (ADI) were used. The comparative potential of the active ingredients of concern in terms of chronic toxicity was assessed using the average annual volume of their estimated use divided by their respective ADI, called chronic hazard potential (CHP) in the present text. The contribution of individual pesticides in different use categories to the total CHP of the user category, was also calculated, using the average annual volume of the active ingredients of all pesticides used during the period 2012-2014. Results On average about 14,000 tonnes of agriculture pesticides, expressed in active ingredients (AI), were annually used in Iran. Herbicides constituted the largest volume (43%), followed by insecticides and acaricides (37%) and fungicides (19%). 0.1% and 47% of the formulated products met the criteria of WHO Class Ib (highly hazardous) and Class II (moderately hazardous) products respectively. Aluminium phosphide and magnesium phosphide were identified as products of primary concern and chlorpyrifos, diazinon and paraquat as products of secondary concern, in terms of their acute human health hazard. No compound in carcinogenicity category 1A or 1B or germ cell mutagenicity/reproduction toxicity category 1A was identified. Six compounds (diazinon, chlorpyrifos, dichlorvos, metam sodium, paraquat and dimethoate) were identified as products with chronic hazard potential based on a low ADI. Conclusions The assessment identified and prioritized agriculture pesticide used in Iran in terms of their acute and chronic hazard to human health for re-registration scheme recently established by PPO and for risk mitigation. It also set priority for research into development of alternative products and practices to minimize pesticide risks. Chronic hazard potential - amount of use adjusted with toxicity may serve as a useful point of reference for trend analysis also in the use of less hazardous agricultural pesticide products.

Exposure to aluminum at work is widespread, and people are exposed to several species of aluminum, which differ markedly as to the kinetics and toxicity. Especially welding of aluminum is widely applied and continuously expanding. Inhalation of fine particles of sparsely soluble aluminum results in the retention of deposited particles in the lungs. From the lungs, aluminum is released to the blood and distributed to bones and the brain, and excreted to urine. Soluble aluminum compounds are not accumulated in the lungs. Neurotoxicity is the critical effect of exposure to sparsely soluble aluminum compounds. Studies on workers exposed to aluminum welding fumes have revealed disturbances of cognitive processes, memory and concentration, and changes in mood and EEG. Early pulmonary effects have been observed among aluminum powder-production workers using high-resolution computed tomography. The primary objective of aluminum biomonitoring (BM) is to help prevent the formation of aluminum burden in the lungs and thereby to prevent harmful accumulation of aluminum in target organs. BM of aluminum can be effectively used for this purpose in the production/use of aluminum powders, aluminum welding, as well as plasma cutting, grinding, polishing and thermal spraying of aluminum. BM of aluminum may also be similarly useful in the smelting of aluminum and probably in the production of corundum. BM can help identify exposed individuals and roughly quantitate transient exposure but cannot predict health effects in the production/use of soluble aluminum salts. For urinary aluminum (U-Al) we propose an action limit of 3 µmol/L, corrected to a relative density of 1.021, in a sample collected preshift after two days without occupational exposure, and without use of aluminum-containing drugs. This value corresponds roughly to 2.3 µmol/g creatinine. Compliance with this limit is expected to protect the worker against the critical effect of aluminum in exposure to sparsely soluble aluminum dusts, the cognitive function of the central nervous system. For serum aluminum (S-Al), we do not propose an action limit because S-Al is less sensitive as an indicator of aluminum load.

The present study describes the effects of tetraethyl lead on various drug metabolizing enzymes in different tissues of the rat. Tetraethyl lead was administered intraperitoneally to rats (250 mumol/kg) on two consecutive days. The animals were killed on day 3. Tetraethyl lead-treatment decreased the concentration of hepatic cytochrome P-450 (to 45 per cent of the control), the hepatic activity of aryl hydrocarbon hydroxylase (to 41 per cent of the control) and ethoxycoumarin deethylase (to 45 per cent of the control). Epoxide hydratase activity was enhanced in the liver (1.3-fold), kidney (3.3-fold), and small intestinal mucosa (4.7-fold). The activity of glutathione S-transferase decreased in the liver (to 69 per cent of the control) but increased in the kidney (1.5-fold) and small intestinal mucosa (1.7-fold). The glucuronidation of o-aminophenol was enhanced (2.2-fold) in the kidney of tetraethyl lead treated rats. It is concluded that exposure to tetraethyl lead brings about widespread changes in the ability of mammals to detoxify foreign compounds.

Both drug oxidation (cytochrome P-450, and the overall hydroxylation reactions aryl hydrocarbon hydroxylase and p-nitroanisole O-demethylase) and glucuronidation (UDPglucuronosyltransferase both with p-nitrophenol and 4-methylumbelliferone as aglycones) were enhanced by administering a single intraperitoneal dose of 3,4-benzpyrene to rats. The flavoprotein component in the microsomal monooxygenase system, NADPH cytochrome c reductase, was not influenced by 3,4-benzpyrene administration. The intragastric administration of carbon tetrachloride (1 ml/kg body weight) almost totally blocked the microsomal drug oxidation and also suppressed the enhancement of both mixed function oxidase and UDPglucuronosyltransferase by 3,4-benzpyrene. The inhibitor of heme synthesis, hematin, and inhibitor of cytochrome P-450 dependent metabolism, SKF 525-A, also suppressed the enhancement of both microsomal mixed function oxidase and UDPglucuronosyltransferase achieved by 3,4-benzpyrene administration.

Microsomes were prepared from the liver, kidney and lung of phenobarbital or 20-methylcholanthrene treated and control rats with the conventional ultracentrifugation and calcium aggregation methods. The two methods were compared as to the yield of microsomal protein, amount of cytochrome P-450/448 and activity of UDP-GLUCURONOSYLTRANSFERASE, BENZOPYRENE HYDROXYLASE AND P-NITROANISOLE O-demethylase. The absolute amount of cytochrome P-450/448 (nmol/g wet weight), as well as the enzymatic activities dependent on it (nmol produced/g wet weight) did not differ significantly in any tissue of either treated or control animals nor did that of UDPglucuronosyltransferase. However, the ultracentrifugation method resulted in a slightly smaller yield of the hepatic microsomal protein and a correspondingly higher yield of cytochrome P-450/448 per mg protein as well as higher specific enzymatic activities of both the consecutive drug biotransformation reactions studied. The specific activity of UDPglucuronosyltransferase in digitonin treated microsomes was twice as high in the conventional microsomes as in the calcium aggregated microsomes; no differences was found in the trypsin treated microsomes. The specific activity of the hepatic benzpyrene hydroxylase of the benzpyrene treated animals in the calcium harvested microsomes was 55 per cent of that in the ultracentrifugated microsomes.

Both 3-methylcholanthrene and phenobarbital increased the 0-demethylation of p-nitroanisole in rat liver microsomes (9-fold and 6-fold, respectively), whereas 3-methylcholanthrene alone was able to enhance the aryl hydrocarbon hydroxylase activity (13-fold). When the inducers were administered to rats in combination, the enhancement in p-nitroanisole 0-demethylase activity was greater and in aryl hydrocarbon hydroxylase was smaller than when administered singly. Both 3-methylcholanthrene and phenobarbital also enhanced the microsomal UDP glucuronyltransferase activity when measured after in vitro activation of the latent enzyme. The pretreatment of rats with the combination brought about no additional effect, when calculated on a microsomal protein basis. If calculated on 100 gram of body weight basis, however, an additive effect was observed in UDP glucuronyltransferase activity due to the effects of the inducers on the liver weight-body weight ratio.

Risk characterization comprises hazard characterization and exposure assessment. Hazard characterization may not be based on human data alone, as these data (1) are seldom available, (2) are quite insensitive in identifying the hazards, and (3) mostly lack reliable exposure-response information. Thus epidemiological information needs to be complemented with information from experimental animals and in vitro systems. These observations suffer from the necessity for species-to-species extrapolation, which is often based on weakly based generic default values. Default values may be replaced by chemical-specific uncertainty factors, but need to be applied cautiously and preferably in a predetermined framework with transparent guidance on what constitutes reliable evidence. Structure-activity relationships (SARs) are useful in setting priorities for hazard characterization and data generation, but seldom alone constitute a sufficient basis for quantitative hazard characterization. Little progress has been made in the assessment of the hazards from multiple simultaneous or successive exposures. Information on the exposure of the population whose risks are to be assessed relies predominantly on models of varying complexity. In the assessment of exposure to elements, speciation and bioavailability are important parameters for which the information often is limited.

Commercial sources of platinum are sulfide and arsenide minerals and, increasingly, recycled platinum. The main source of platinum in the environment is release from vehicle catalysts, and platinum concentrations near highways and urban areas have gradually increased. In occupational exposure, the form of platinum is mainly coordination complexes, most often with chlorine as a ligand, whereas the platinum released from automotive catalysts is metallic or oxidic. The acute toxicity of platinum compounds depends mainly on their solubility, with soluble platinum salts being more toxic than compounds with lower solubility, such as oxides. Chloroplatinates are irritating to the eyes and skin. The main health effect of platinum compounds is sensitization. Platinum salt sensitivity is manifested as conjunctivitis, rhinitis, and asthma. The allergenic potency of platinum compounds seems to be limited to coordination complexes containing halogen ligands as leaving groups, with hexa- and tetrachloroplatinates being the most potent sensitizers. Neutral coordination complexes such as diamminedichloroplatinum do not seem to be allergenic. Bromine and iodine analogs of platinates may cause sensitization but seem to be less potent. The mechanism of platinum salt allergy is likely to be type 1 (i.e. involves immunoglobulin E). Atopic constitution is not associated with susceptibility to platinum sensitization. Smokers have a higher risk of platinum sensitization. No health effects from environmental exposure to platinum have been reported. With the exception of platinum-containing chemotherapeutic drugs such as cisplatin (cis-diamminedichloroplatinum), no relevant human or experimental data are available on the potential carcinogenicity or teratogenicity of platinum compounds. Cisplatin and other platinum-containing chemotherapeutic drugs are genotoxic in a variety of test systems, and other platinum compounds have even induced mutations in vitro (but not in vivo). Limited data are available on the toxicity of platinum nanoparticles despite their increasing use in different applications. Platinum compounds used as anticancer drugs such as cisplatin and its analogs are not covered in detail in this chapter; they are discussed only when it is informative with respect to structure-activity relationships.

Biological monitoring (BM; synonym, biomonitoring) was developed for the assessment of the health risks from exposure to metals in the work environment, and the approaches and concepts of biomonitoring are derived from such exposures. At present, biomonitoring is increasingly used to assess exposure from the environment. Biomonitoring and the assessment of external exposure are complementary activities, where external exposure assessments are much more widely applied, especially when the number of chemicals concerned is considered; environmental analysis also offers the distinct advantage of speciation analysis, which is very poorly developed for biomonitoring. Biomonitoring, on the other hand, provides information on exposure from all sources and via all absorption routes, and also considers accumulation of the chemical in the body. Biomonitoring using exposure biomarkers thus considers interindividual differences in absorption, whereas the use of effect biomarkers also considers interindividual differences in susceptibility. Few effect biomarkers, however, have been validated. Biomarkers of susceptibility have so far not been adapted for routine use in metal toxicology. The major challenges of biomonitoring are the development of (preferably noninvasive) monitoring methods, which are inexpensive enough to be applied at a frequency that makes possible the meaningful biomonitoring of metals with a short half-time; the development of exposure biomarker guidance values specific to individual species of different metals; expansion of the repertoire of validated effect biomarkers; and the validation and application to effect monitoring of the “omic” technologies. Promotion of the scientifically sound use of biomonitoring in chemical risk management, for example as a tool to control the effectiveness of risk management measures, is also one of the today’s challenges.

Gold is a rare, noble metal. It does not oxidize and occurs mainly in the elemental form; gold salts are not stable in aqueous solutions but tend to precipitate as elemental gold. In contrast, coordination complexes of gold are stable, and have the potential to pose a health hazard. Gold has been analyzed using flame atomic absorption (ore samples), flameless atomic absorption spectrometry (biological specimens of patients treated with gold), or inductively coupled plasma mass spectrometry (water samples, urine and blood from people not iatrogenically exposed). Levels of human exposure to gold from the air, food, and water are very low. Similarly, occupational exposure remains low. Measurable exposure can be caused by dental inlays, crowns, and bridges, but even this type of exposure apparently has little toxicological significance. Some thiol compounds of gold have been used extensively in medicine, notably in the treatment of rheumatic arthritis. They are rapidly metabolized, with those given orally apparently already metabolized before absorption. The coordination complex, Au(CN)2−, seems to be a common metabolite of all of these drugs, although its proportion of all metabolites is not known. Gold nanoparticles are extensively studied for use in different biomedical applications, including biomedical imaging methods, photothermal therapy, and targeted drug delivery. Particle size, surface properties, and route of exposure affect the absorption and distribution of gold nanoparticles. Gold nanoparticles have been shown to be taken up from the lungs and gastrointestinal tract. After intravenous administration, smaller particles show more widespread tissue distribution than larger gold nanoparticles, which tend to accumulate mainly in liver and spleen. Large doses, in the order of several grams, have been used in the treatment of rheumatic arthritis parenterally, and the incidence of side effects has been high. The most common effects are related to the skin and mucous membranes; the most serious, even fatal, effect is the suppression of bone marrow, aplastic anemia (anemia, thrombocytopenia, and agranulocytosis). Effects of gold therapy on the kidney are relatively frequent, and most usually occur in the form of membranous glomerulonephritis. This and other kidney effects are usually reversible upon cessation of the therapy. Gold-induced lung damage is rare, and usually reversible, but fatal cases have also been described. Mild gastrointestinal symptoms are very frequent; serious colitis is very rare, but may be fatal. In repeated dose studies in experimental animals, the kidney is the main target organ of gold toxicity; at high doses, tubular necrosis, and at lower doses, kidney cortex fibrosis has been observed. Such findings have not been reported in exposed humans. Repeated intramuscular (i.m.) administration of gold thiomalate has caused local injection site sarcomas in rats. Long-term i.m. administration of auranofin and triethylphosphine gold orally or aurothiomalate caused renal adenomas in rats. High doses of gold were embryotoxic and induced teratogenic effects in rats and rabbits. No information could be found on the mutagenic effects of gold compounds. Gold nanoparticles have generally shown low toxicity after oral or parenteral administration. Particle size, shape, and surface coating may modify the toxicity of gold nanoparticles. Subchronic inhalation exposure of rats to 4-5 nm gold nanoparticles resulted in only mild lung inflammation at doses ≥ 20 μg/m3. Gold nanoparticles have generally been negative in genotoxicity studies. Reproductive toxicity of gold nanoparticles has not been adequately studied but, according to available information, placental penetration of gold nanoparticles is limited. Interindividual variation in gold concentrations in the blood and urine are related to the internal exposure to gold from dental appliances, and this variation makes it impossible to use biological monitoring to meaningfully assess environmental or even occupational exposure to gold. While there are some studies indicating an association between therapeutic or adverse effects of gold and concentrations of gold in biological media, the majority of studies on the subject have not observed any such association. At present, therefore, biological monitoring cannot assist in predicting the outcome of gold therapy or the adverse effects of gold. In gold-mining operations, exposure to gold is negligible but, depending on the ore type and quality and mining technology, exposure to silica, mercury, arsenic, radon, diesel engine exhaust, lead, and cyanide are possible. In different parts of the world, very high incidences of even severe silicosis and subsequent pulmonary tuberculosis have been observed. Especially in small-scale gold mining, large amounts of mercury have been traditionally used, and are still being used, especially in the informal sector. Very significant exposure to inorganic mercury among miners and their families has been reported in many countries on all continents. In several instances, even outright mercury poisonings have occurred. In the vicinity of artisanal gold-mining areas, exposure to methylmercury has been demonstrated in different parts of the world. Release of arsenic to the environment from gold-mining activities has been well documented in many places, and even arsenic exposure, measured from arsenic concentrations in body tissues and fluids, has been documented in some populations. Spills and leakages of cyanide from gold mines have caused several environmental accidents, with very serious effects on aquatic wild life. Exposure to lead from the ore in an area of artisanal gold mining has caused a large and serious epidemic of lead poisoning, with many fatalities.

Humans live on chemicals, and no exposure to any chemicals is incompatible with life. Chemicals produced by different organisms are in no basic way different from the man-made chemicals, and often chemicals are produced by both. Natural chemicals include the most potent acutely toxic chemicals known, and also include very potent mutagens and human carcinogens. Thus the fact that a chemical is 'natural' does not mean that it is any safer than a man-made chemical, and the fact that a chemical is man-made does not make it any more harmful than 'natural' chemicals. Exposure to chemicals varies widely, to a large variety of chemicals people are exposed from the environment, via drinking water, food and inhaled air and exposure e.g. at the work-place is only quantitatively different from the exposure of the general public. Zero exposure is meaningless without an operational definition. It is a major challenge to the society to determine what is the safe exposure level to different chemicals, and for chemicals for which no exposure level is safe, to define the acceptable risk, and in both cases, make sure that the exposure limits thus determined are complied with.

The purpose of these guidelines is to provide concise guidance on the planning, performing and interpretation of studies to monitor groups or individuals exposed to genotoxic agents. Most human carcinogens are genotoxic but not all genotoxic agents have been shown to be carcinogenic in humans. Although the main interest in these studies is due to the association of genotoxicity with carcinogenicity, there is also an inherent interest in monitoring human genotoxicity independently of cancer as an endpoint. The most often studied genotoxicity endpoints have been selected for inclusion in this document and they are structural and numerical chromosomal aberrations assessed using cytogenetic methods (classical chromosomal aberration analysis (CA), fluorescence in situ hybridisation (FISH), micronuclei (MN)); DNA damage (adducts, strand breaks, crosslinking, alkali-labile sites) assessed using bio-chemical/electrophoretic assays or sister chromatid exchanges (SCE); protein adducts; and hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations. The document does not consider germ cells or gene mutation assays other than HPRT or markers of oxidative stress, which have been applied on a more limited scale.

Vinyl chloride (VC) is both a known carcinogen and a regulated chemical, and its production capacity has almost doubled over the last 20 years, currently 27 million tons/year worldwide. According to recent reports it is still a cause for concern. VC has been found as a degradation product of chloroethylene solvents (perchloroethylene and trichloroethylene) and in landfill gas and groundwater at concentrations up to 200 mg/m(3) and 10 mg/L, respectively. Worldwide occupational exposure to VC still seems to be high in some countries (e.g., averages of approximately 1,300 mg/m(3) until 1987 in one factory), and exposure may also be high in others where VC is not regulated. By combining the most relevant epidemiologic studies from several countries, we observed a 5-fold excess of liver cancer, primarily because of a 45-fold excess risk from angiosarcoma of the liver (ASL). The number of ASL cases reported up to the end of 1998 was 197 worldwide. The average latency for ASL is 22 years. Some studies show a small excess risk for hepatocellular carcinoma, and others suggest a possible risk of brain tumors among highly exposed workers. Lung cancer, lymphomas, or leukemia do not seem to be related to VC exposure according to recent results. The mutation spectra observed in rat and human liver tumors (ASL and/or hepatocellular carcinoma) that are associated with exposure to VC are clearly distinct from those observed in sporadic liver tumors or hepatic tumors that are associated with other exposures. In rats, the substitution mutations found at A:T base pairs in the ras and p53 genes are consistent with the promutagenic properties of the DNA adduct 1,N(6)-ethenoadenine formed from VC metabolites. Risk assessments derived from animal studies seem to overestimate the actual risk of cancer when comparing estimated and reported cases of ASL. Images Figure 1 Figure 2

Objective and methods: The exposure of Finnish tank lorry drivers to methyl tert-butyl ether (MTBE) and tert-amyl methyl ether (TAME) during loading of gasoline was studied using biological and breathing-zone sampling. During the field measurements – in October 1994 and August 1995 – the gasolines (95, 98, 99 RON) contained MTBE to 5.2–11.8% and TAME to 0–6%. Results: The geometric mean (GM) breathing-zone concentration of MTBE was 4.3 mg/m3 (n= 15) in October and 6.4 mg/m3 (n= 20) in August. The GM concentration of TAME, measured only in August, was 0.98 mg/m3. The mean loading/sampling times were 37 and 35 min, the mean wind speeds were 0.8 and 0.6 m/s, and the mean air temperatures were −4.9° and +14.1 °C, respectively. Blood samples collected on average at 20 min after gasoline loading/exposure showed an MTBE concentration of 143 nmol/l (GM, n= 14) in October and 213 nmol/l (GM, n= 20) in August. Pearson's coefficient of correlation (r) between the MTBE breathing-zone concentrations and MTBE in blood was 0.86 (P= 0.0001) in October and 0.81 (P= 0.00001) in August. No correlation was found between MTBE in air and the metabolite tert-butanol (TBA) in blood. MTBE, but not TBA, in urine samples collected on average at 2.5 h after exposure showed a correlation with MTBE in air. The concentrations of TAME and its metabolite tert-amyl alcohol were below the quantitation limits (

Objectives: To assess cancer risk among nickel-exposed workers. Methods: We updated cancer incidence among 1388 workers employed for at least 3 months at a copper/nickel smelter and nickel refinery in Harjavalta, Finland. There were 1155 workers exposed to nickel during the period 1960–1985 in the smelter (566 workers), repair shop (239 workers), or refinery (418 workers). Cancer incidence was followed through the files of the Finnish Cancer Registry up to 31 December 1995. For overall cancer and for a priori selected specific cancer types the ratio of observed to expected numbers of cases was computed as a standardized incidence ratio (SIR), controlled for age, gender, and calendar period and using the region-specific rates as a reference. Results: The overall cancer incidence among both nickel-exposed and unexposed subcohorts was at the expected level. A small increase in lung cancer incidence, which reached statistical significance among workers with a latency exceeding 20 years, was observed among the smelter workers exposed to insoluble nickel compounds. Among workers in the refinery, who were exposed primarily to nickel sulfate at levels below 0.5 mg/m3 as well as to low concentrations of other nickel compounds, there was an increased risk for nasal cancer (SIR 41.1, 95% CI 4.97–148), positively associated with latency and duration of employment, and an excess risk for stomach (SIR 4.98, 95% CI 1.62–11.6) and lung (SIR 2.61, 95% CI 0.96–5.67) cancers. Conclusions: Since elevated nasal and lung cancer risks were confined to the refinery, where the primary exposure was to nickel sulfate, it is likely that nickel sulfate is mainly responsible for the elevated respiratory cancer risk. We cannot rule out whether the excess stomach cancer risk is a chance finding, or related to the working environment.

Organic oxygenates, namely, methyl tert-butyl ether (MTBE) and methyl tert-amyl ether (MTAE), are added to gasoline to reduce carbon monoxide in exhausts and to enhance the octane number. The aim of this study was to investigate road-tanker drivers' exposure to oxygenate vapors during road-tanker loading and unloading as well as to evaluate the measurements of these ethers and their metabolites in the urine as a means of assessing the uptake of the ethers. A total of 11 drivers in different parts of Finland were trained to monitor their exposure with personal samplers, to report their working conditions, and to collect their whole-day urine samples. Charcoal tubes of the air samples were analyzed for MTBE, MTAE, benzene, toluene, and aliphatic hydrocarbons. For biological monitoring purposes the two main oxygenates, tertiary ethers MTBE and MTAE, as well as their main metabolites, tertiary alcohols tert-butanol (TBA) and tert-amyl alcohol (TAA), were determined in urine specimens. On average the drivers were exposed to vapors for short periods (21 +/- 14 min) three times during a work shift. The mean concentrations of MTBE and MTAE (mean +/- SD) were 8.1 +/- 8.4 and 0.3 +/- 0.4 mg/m3. The total MTBE uptake during the shift was calculated to be an average of 106 +/- 65 mumol. The mean concentrations of MTBE, TBA, MTAE and TAA detected in the first urine after the work shift were 113 +/- 76, 461 +/- 337, 16 +/- 21, and 40 +/- 38 nmol/l, and those found the next morning, 16 h later, were 18 +/- 12, 322 +/- 213, 9 +/- 10, and 20 +/- 27 nmol/l. The good relationship (r = 0.84) found between MTBE exposure and postshift excretion suggests that urinary MTBE can be used for biological monitoring of exposure, but at the present low level of exposure the corresponding metabolite TBA is not equally reliable. The determination of MTAE and its metabolite TAA in urine is sensitive enough to detect the low degree of exposure to MTAE, but in this study the data were too scarce to allow calculation of the correlations due to very low levels of MTAE exposure.

OBJECTIVES: Assessment of neurophysiological functions in workers with low level exposure to lead and evaluation of the efficacy of bone lead measurements in the prediction of effects of lead. METHODS: Exposure to lead of 60 workers from a lead battery battery factory was estimated from historical blood lead measurements and analysis of lead in the tibial and calcaneal bones with x ray fluorescence. Peripheral and central nervous system functions were assessed by measuring conduction velocities, sensory distal latencies, sensory amplitudes, and vibration thresholds as well as by quantitative measurement of the absolute and relative powers and mean frequencies of different electroencephalograph (EEG) channels. RESULTS: Sensory amplitudes, and to a smaller degree sensory or motor conduction velocities, showed a negative correlation with long term exposure to lead, most clearly with integrated blood lead concentration and exposure time. Vibration thresholds measured in the arm were related to recent exposure to lead, those measured in the leg to long term exposure. The alpha and beta activities of the EEG were more abundant in subjects with higher long term exposure to lead. Calcaneal lead content reflected short term exposure, tibial lead content reflected long term exposure. Blood lead history showed a closer relation with effects of lead than the tibial or calcaneal lead concentrations. CONCLUSIONS: Vibratory thresholds, quantitative EEG, and to a smaller extent the sensory amplitude, provide sensitive measures of effects of lead in occupationally exposed adults. Most accurate estimates of health risks induced by lead can be obtained from a good history of blood lead measurements. If such a history of blood lead concentrations is not available, analysis of bone lead may be used for the assessment of health risks.

The purpose of this study was to compare different biological methods in current use to assess benzene exposure. The methods involved in the study were: benzene in blood, urine and exhaled air, and the urinary metabolites t,t -muconic acid (MA) and S -phenylmercapturic acid ( S -PMA). Blood, urine and exhaled air samples were collected from workers in a benzene plant (pure benzene exposure) and cokery (mixed exposure, e.g. polycyclic aromatic hydrocarbons — PAHs) in an Estonian shale oil petrochemical plant. The benzene in these samples was analysed with a head-space gas chromatograph, and the metabolites MA and S -PMA with a liquid chromatograph using methods developed from published procedures. Some of the values measured in the Estonian shale oil area were high in comparison with those published during the last few years, whereas the values measured in the control group did not show any exposure to benzene except in the smokers group. The highest median exposure was in the benzene factory, 0.9 cm 3 /m 3 TWA (2.9 mg/m 3 ) and the highest individual value was 15 cm 3 /m 3 TWA (49 mg/m 3 ). All biological measurements in this study gave the same assessment about exposure to benzene and correlated highly significantly with each other and with the air measurements ( r = 0.8 or more). In the benzene factory the correlation was good even when calculated from samples with air concentration 3 /m 3 (3.2 mg/m 3 ) in the case of blood benzene and urinary MA. However, for S -PMA it was weak ( r = 0.4) and for benzene in urine and exhaled air it did not exist any more. In the cokery, with mixed exposure, the correlation at low levels was weaker even for blood benzene and urinary MA ( r = 0.6). According to the results in the benzene factory the exposure to pure benzene at the level 1 cm 3 /m 3 (3.25 mg/m 3 ) TWA gave: the blood benzene value about 110 nmol/l (8.6 μg/l), MA 23 μmol/l (3.3 μg/l) or 2.0 mg/g creatinine, S -PMA 58 μg/g creatinine or 0.4 μmol/l (95.7 μg/l), benzene in urine 499 nmol/l (39 μg/l), and benzene in the exhaled air 2.8 nmol/l (0.2 μg/l). In general, the measurement of benzene in blood and in exhaled air, as well as benzene and its metabolites MA and S -PMA in urine, all gave similar results. However, at low exposure level ( 3 /m 3 ) the most reliable analyses were MA in urine and benzene in blood.

A reliable and sensitive graphite furnace atomic absorption spectrometry (GFAAS) method with Zeeman background correction was developed for the analysis of aluminium in serum and urine in the biological monitoring of aluminium exposure. The method is based on platform atomisation in pyrolytically coated graphite tubes after fourfold dilution with nitric acid. For serum analysis, a matrix matched standard curve is prepared and for urine the method of standard additions is used. The within-run imprecision (C.V.) for serum and urine was 3% and 5%, and the between-day imprecision, 6% and 7.2%, at a concentration level of 4.0 mumol/l. The between-day imprecision for urinary aluminium was 15.7% at a concentration level of 0.24 mumol/l. The detection limits were 0.02 mumol/l for serum and 0.07 mumol/l for urine. During 1 year of participation in TEQAS external quality assessment scheme of the Robens Institute for Health and Safety (Guildford, UK) for serum aluminium the maximum cumulative performance score was achieved. For urinary aluminium a certificate in the external quality control scheme of the German Society of Occupational Medicine was obtained. The mean concentration of aluminium in a non-exposed population, who did not use antacid drugs, was 0.06 mumol/l (S.D. 0.03, range 0.02-0.13, n = 21) in serum, and 0.33 mumol/l (S.D. 0.18, range 0.07-0.82, n = 44) in urine. The upper reference limit for aluminium in a healthy, non-exposed population was estimated to be 0.1 mumol/l in serum and 0.6 mumol/l in urine.

Past and present exposure to nickel was studied in an electrolytic nickel refinery, where an increased incidence of nasal cancer had been reported, using nickel analyses in air, blood and urine. Genotoxic effects were studied using analysis of micronuclei from acridine orange-stained smears from the buccal mucosa of the workers. Workers used respirators or masks in tasks where the exposure was expected to be high. Inside the mask, nickel concentrations were 0.9-2.4 micrograms m-3 in such tasks. In those tasks where masks were not used, nickel concentrations in the breathing zone were 1.3-21 micrograms m-3. Air-borne nickel concentrations (stationary sampling) varied between 230 and 800 micrograms m-3 in 1966-1988 with no systematic change; thereafter lower concentrations (170-460 micrograms m-3) have been observed. After-shift urinary concentrations of nickel were 0.1-2 mumol l-1; they showed no correlation with nickel concentrations in the air. Concentrations of nickel in the urine were still elevated after a 2-4 week vacation. The frequency of micronucleated epithelial cells in the buccal mucosa of nickel refinery workers was not significantly elevated by comparison with referents. No relationship was observed between micronucleus frequencies and levels of nickel in air, urine or blood.

An occupational hygiene survey was made in 38 nickel plating shops in Finland and exposure to nickel was studied by means of biological measurements and, in three shops, by using air measurements. The average after-shift urinary nickel concentration of 163 workers was 0.16umoll.~' (range 0.001-4.99 umol I."*1). After the 1-5 week vacation the urinary nickel concentration was higher than the upper reference limit of non-exposed Finns indicating that a part of water-soluble nickel salts is accumulated in the body. Urinary nickel concentrations in the shops considered clean in the industrial hygiene walk-through were not different from those observed in the shops considered dirty. The correlation between the concentrations of nickel in the air and in the urine was low, and the amount of nickel excreted in the urine exceeded the calculated inhaled amounts, indicating exposure by other routes such as ingestion. © 1997 British Occupational Hygiene Society. Published by Elsevier Science Ltd.

A worksite survey was conducted in all 38 Finnish electroplating plants. All workers (n = 163) who worked with nickel plating (bath workers, hangers and solution makers) were interviewed with a questionnaire about symptoms of nickel dermatitis, hand dermatitis, and about protective measures, atopy, etc. Patch testing with nickel sulfate was done with the TRUE TestTM method. All the workers, 94 men and 69 women, answered the questionnaire. The mean age of women was 41.1 years, and of men 43.1 years, respectively. Men had longer occupational exposure to nickel (14 years) than women (10 years). Most workers used protective gloves. 35% of women and 30% of men reported present or past hand dermatosis. 19% reported a history of atopic dermatitis. 15% of women (n = 8) and 4% (n = 2) of men had an allergic patch test reaction to nickel sulfate. 70% of those with an allergic patch test reaction to nickel reported past or present hand eczema. The prevalence of nickel allergy among the electroplaters was similar to that of patients in patch test clinics in Finland. An allergic patch test reaction to nickel sulfate does not necessarily oblige an electroplater to change jobs.

Analysis of 2-thiothiazolidine-4-carboxylic acid (TTCA), a metabolite of carbon disulfide (CS2), is used in the biological monitoring exposure to CS2 at work. In order to clarify the metabolic reasons for individual variation in the urinary excretion of TTCA, the latter was studied in rats pretreated with model cytochrome P450 (CYP) enzyme inducers or glutathione (GSH) depletors. Ethanol, phenobarbital (PB) or 3-methylcholanthrene (MC) did not increase 24-h TTCA output following CS2 inhalation (50 or 500 ppm, 6h). After oral dosing (10 mg/rat), PB had an inhibiting effect on the excretion rate of TTCA. Tissue GSH depletors phorone, L-buthionine-(RS)-sulfoximine (BSO) and diethylmaleate (DEM) decreased TTCA excretion in rats given an oral dose (10 mg/rat) of CS2. The initial inhibition by phorone and DEM was reversed after 6 h and from 12 h onward the TTCA in urine exceeded the control level, an effect not seen with BSO. The proportion of CS2 excreted in urine as TTCA within 24 h was 1.7% in control rats and 1% after BSO treatment, 1.3% after PB, 1.7% after acetone, 1.8% after MC, 2.0% after phorone and 2.5% after DEM treatment. The amount of TTCA in urine increased with the CS2 dose in a non-linear fashion: 1.6 mumol (50 ppm/6 h) vs. 4.9 mumol (500 ppm/6 h), and 0.2 mumol (1 mg/kg) versus 3.6 mumol (100 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Manganese is chemically reactive metal with physical characteristics varying from hard and brittle to soft and flexible. Main use of manganese is in steel production. The major non-metallurgical use of manganese is as manganese dioxide for producing dry-cell batteries. Organic manganese compounds include methylcyclopentadienyl manganese tricarbonyl used as an additive to gasoline, ethylene-bis-dithiocarbamate pesticides maneb and mancozeb, and an image enhancer manganese dipyridoxyl diphosphate. Main health hazard of manganese is neurotoxicity. Recent epidemiological studies show that subtle neurobehavioral effects, including fine deficits in motor performance and in attention, can be seen at exposure levels of ≥0.02–0.03 mg Mn/m3 as respirable dust. Rhenium is characterized by a very high melting temperature and density. Very few data exist on the toxicity of rhenium. Keywords: manganism; neurotoxicity; welding; ferroalloy production; manganese dioxide; methylcyclopentadienyl manganese tricarbonyl ; perrhenates

In this work a high-performance liquid chromatographic method is described that is reliable and practical for use in routine biological monitoring of exposure to styrene. The method uses a modern diode array detection technique by which mandelic and phenylglyoxylic acids can be measured simultaneously using different wavelengths. The liquid chromatographic method was compared to a gas chromatographic method developed for the analysis of mandelic, phenylglyoxylic and para-hydroxymandelic acids. The methods gave results consistent with each other. These two methods were then used to check the stability of the main metabolites of styrene, especially of phenylglyoxylic acid, in urine samples stored at +6 degrees C or at -18 degrees C for periods up to 70 days. None of the frozen samples showed any significant decrease in the phenylglyoxylic acid concentration, whereas at 6 degrees C one of the samples showed a reduction of 46% after 1 month.

The follow-up of environmental carbon disulfide (CS2) exposure and urinary excretion of 2-thiothiazolidine-4-carboxylic acid (TTCA) among 20 operatives over a 4-day working week in two viscose producing factories confirmed earlier observations that TTCA is a sensitive and reliable indicator of exposure to CS2. Exposure to as low as 0.5-1.0 ppm (1.6-3.2 mg/m3) of CS2 (8-hour time-weighted average [TWA]) was associated with detectable amounts of TTCA in end-of-shift urine. Moreover, the excretion of TTCA, relative to estimated CS2 uptake, appeared surprisingly constant in the studied work force. Approximately 3% (range 2-6.5%) of absorbed CS2 was detected in urine as TTCA. The proportional TTCA excretion did not show dose dependency in the estimated CS2 dose range which varied by about 20-fold. TTCA elimination exhibited both a fast (T 1/2 6 hour) and a slow (T 1/2 68 hour) phase. The slow elimination is compatible with a high lipid solubility and reversible protein binding of CS2. Consequently, urinary excretion of TTCA, relative to CS2 exposure, increased by about a third during the workweek. Urinary TTCA concentration of 4.5 mmol/mol creatinine in a postshift sample corresponded to a TWA exposure to 10 ppm CS2 towards the end of the working week.

To obtain reference values for blood and serum manganese levels, blood specimens were collected from 29 men and 36 women. Mn in blood showed a normal distribution; its upper 97.5% limit in blood was 0.38 mumol/l. Mn in serum showed a skewed distribution, which did not differ from the normal one after logarithmic transformation. The respective reference limit was 19 nmol/l. In both specimens, the levels of Mn were significantly lower in men than in women. To obtain reference values for Mn in urine, midday urine specimens were collected from 58 men and 96 women. Mn in urine also showed a skewed distribution, and the upper 97.5% limit was 38 nmol/l. The levels of Mn in blood and urine were statistically significantly higher in manual metal arc (MMA) welders of mild steel (MS) than in the reference populations. Five MMA/MS welders were subjected to a further study in which the ambient intramask Mn levels and urinary Mn excretion were monitored throughout a full working week. For two welders the correlation of Mn in urine specimens voided in the afternoon was good with the before noon Mn concentrations in the hygienic measurements; for the rest the correlation was minimal. Mn in diurnal urine specimens collected in six portions showed fluctuation if specific gravity or creatinine in urine was used to standardize for the urinary flow, but it was less evident for urinary Mn excretion rate. Our results seem to indicate that the measurement of Mn in urine or blood may be used for monitoring Mn exposure in MMA/MS welders only at the group level.

The excretion and conjugation of chlorophenols were studied in workers exposed to 2,4,6-tri-, 2,3,4,6-tetra-, and pentachlorophenolates, the main components of the chlorophenolate product manufactured by direct chlorination of phenol. The workers were exposed in two different saw mills in which sodium chlorophenolate was used for treatment of lumber during the warm season. Urine specimens were collected at the end of the treatment season as well as at the start of a new treatment period in the spring. Serum specimens were collected towards the end of the treatment period. Total and unconjugated chlorophenols were analyzed with a gas chromatographic method. The maximal concentrations of urinary 2,4,6-tri-, 2,3,4,6-tetra- and pentachlorophenol at the end of the lumber-treatment period were 1-11.8, 3.4-17.3, and 0.2-0.9 mumol/l, respectively, and the average apparent half-times calculated using a one-compartment model were 18 h, 4.3 days and 16 days, respectively. For 2,3,4,6-tetrachlorophenol, the data of some subjects showed a better fit with a two-compartment model; the corresponding half-times were 5.3 and 26 days. During the continuous-exposure period the average serum levels of tetra- and pentachlorophenol were rather similar before and after the working day: 2.79 +/- 1.78 mumol/l for tetrachlorophenol and 0.85 +/- 0.4 mumol/l for pentachlorophenol. Renal clearance values for tetra- and pentachlorophenol were related to urine flow and indicated tubular reabsorption. At low concentrations, sulfate conjugation was dominant. With increasing chlorophenol concentrations the proportion of glucuronide conjugation was increased, especially for pentachlorophenol.

Healthy male volunteers were exposed via inhalation to gasoline oxygenates methyl tert-butyl ether (MTBE) or tert-amyl methyl ether (TAME). The 4-hr exposures were carried out in a dynamic chamber at 25 and 75 ppm for MTBE and at 15 and 50 ppm for TAME. The overall mean pulmonary retention of MTBE was 43 +/- 2.6%; the corresponding mean for TAME was 51 +/- 3.9%. Approximately 52% of the absorbed dose of MTBE was exhaled within 44 hr following the exposure; for TAME, the corresponding figure was 30%. MTBE and TAME in blood and exhaled air reached their highest concentrations at the end of exposure, whereas the concentrations of the metabolites tert-butanol (TBA) and tert-amyl alcohol (TAA) concentrations were highest 0.5-1 hr after the exposure and then declined slowly. Two consecutive half-times were observed for the disappearance of MTBE and TAME from blood and exhaled air. The half-times for MTBE in blood were about 1.7 and 3.8 hr and those for TAME 1.2 and 4.9 hr. For TAA, a single half-time of about 6 hr best described the disappearance from blood and exhaled air; for TBA, the disappearance was slow and seemed to follow zero-order kinetics for 24 hr. In urine, maximal concentrations of MTBE and TAME were observed toward the end of exposure or slightly (or = 1 hr) after the exposure and showed half-times of about 4 hr and 8 hr, respectively. Urinary concentrations of TAA followed first-order kinetics with a half-time of about 8 hr, whereas the disappearance of TBA was slower and showed zero-order kinetics at concentrations above approx. 10 micro mol/L. Approximately 0.2% of the inhaled dose of MTBE and 0.1% of the dose of TAME was excreted unchanged in urine, whereas the urinary excretion of free TBA and TAA was 1.2% and 0.3% within 48 hr. The blood/air and oil/blood partition coefficients, determined in vitro, were 20 and 14 for MTBE and 20 and 37 for TAME. By intrapolation from the two experimental exposure concentrations, biomonitoring action limits corresponding to an 8-hr time-weighted average (TWA) exposure of 50 ppm was estimated to be 20 micro mol/L for post-shift urinary MTBE, 1 mu mol/L for exhaled air MTBE in a post-shift sample, and 30 micro mol/L for urinary TBA in a next-morning specimen. For TAME and TAA, concentrations corresponding to an 8-hr TWA exposure at 20 ppm were estimated to be 6 micro mol/L (TAME in post-shift urine), 0.2 micro mol/L (TAME in post-shift exhaled air), and 3 micro mol/L (TAA in next morning urine).

Biomarkers of exposure, parent chemicals, metabolites, and also hemoglobin and DNA (deoxyribonucleic acid) adducts, even urinary mutagenicity, have been used successfully to identify exposed persons, follow-up exposure, and quantitatively assess exposure. Some have been validated as indicators of health risk. The avenues for future biomarkers of exposure are in the development of robust, simple, and inexpensive semiquantitative methods for daily use on every worker for assuring that no (excessive) exposure takes place. Some biomarkers of effect have also been well validated and are widely used in routine monitoring activities. However, with the exception of cholinesterase inhibitors, biomarkers of effect offer little advantage over the analysis of the chemical itself. Their use will be limited to carefully planned ad hoc studies. Biomarkers of susceptibility currently have no practical application in worker health protection. Biomarker research should concentrate on validating methods, in terms of the prediction of health effects, and on elucidating exposure-biomarkers concentration relationships.

OBJECTIVE: To evaluate the neuropsychological effects of current low level and previous higher levels of exposure to lead and evaluate the relation between effects of lead and bone lead. METHODS: A neuropsychological test battery was given to 54 storage battery workers with well documented long term exposure to lead. The effect was studied in two subgroups: those whose blood lead had never exceeded 2.4 mmol/l (the low BPbmax group, n = 26), and those with higher exposure about 10 years earlier (the high BPbmax group, n = 28). In both groups, the recent exposure had been low. Correlations between the test scores and the indices of both long term and recent exposure--including the content of lead in the tibial and calcaneal bone--and covariance analyses were used to assess the exposure-effect relation. Age, sex, and education were controlled in these analyses. RESULTS: Analyses within the low BPbmax group showed a decrement in visuospatial and visuomotor function (block design, memory for design, Santa Ana dexterity), attention (digit symbol, digit span), and verbal comprehension (similarities) associated with exposure to lead and also an increased reporting of subjective symptoms. The performance of the high BPbmax group was worse than that of the low BPbmax group for digit symbol, memory for design, and embedded figures, but there was no reporting of symptoms related to exposure, probably due to selection in this group. No relation was found between the output variables and the tibial lead concentration. The calcaneal lead concentrations were related to the symptoms in the low BPbmax group. CONCLUSIONS: Neuropsychological decrements found in subjects with high past and low present exposure indicate that blood lead concentrations rising to 2.5- 4.9 mmol/l cause a risk of long lasting or even permanent impairment of central nervous system function. Milder and narrower effects are associated with lower exposures; their reversibility and time course remain to be investigated. History of blood lead gives a more accurate prediction of the neuropsychological effects of lead than do measurements of bone lead.

Publisher Summary This chapter discusses the basic principles and methods, starting with sampling, sample storage and sample treatment. These steps are important for each analytical procedure. Human specimens are analyzed for trace elements in order to find out whether there is a deficiency of an element or if there is excessive exposure to an element. When trace elements are analyzed in living subjects, the specimens that are available are limited; usually only blood, urine, feces or hair is available. The physiological factors that affect the relationship between the concentrations of a trace element in the target tissues and in the body fluids are very important. Various aspects on sources of error in sample collection and storage for trace element analysis are reviewed. Especially toxic concentrations of trace elements are not constant, but change with time, and often show an exposure-related fluctuation. The variations associated with specimen collection and storage is discussed by reviewing the potential of a number of modern trace analytical methods such as atomic absorption and emission spectrometry.

Measurements of bone lead concentrations in the tibia, wrist, sternum, and calcaneus were performed in vivo by x ray fluorescence on active and retired lead workers from two acid battery factories, office personnel in the two factories under study, and control subjects. Altogether 171 persons were included. Lead concentrations in the tibia and ulna (representative of cortical bone) appeared to behave similarly with respect to time but the ulnar measurement was much less precise. In an analogous fashion, lead in the calcaneus and sternum (representative of trabecular bone) behaved in the same way, but sternal measurement was less precise. Groups occupationally exposed to lead were well separated from the office workers and the controls on the basis of calculated skeletal lead burdens, whereas the differences in blood lead concentrations were not as great, suggesting that the use of concentrations of lead in blood might seriously underestimate lead body burden. The exposures encountered in the study were modest, however. The mean blood lead value among active lead workers was 1.45 mumol l-1 and the mean tibial lead concentration 21.1 micrograms (g bone mineral)-1. The kinetics of lead in the tibia appeared to be noticeably different from that in the calcaneus. Tibial lead concentration increased consistently both as a function of intensity of exposure and of duration of exposure. Calcaneal lead concentration, by contrast, was strongly dependent on the intensity rather than duration of exposure. This indicated that the biological half life of lead in calcaneus was less than the seven to eight year periods into which the duration of exposure was split. Findings for retired workers clearly showed that endogenous exposure to lead arising from skeletal burdens accumulated over a working lifetime can easily produce the dominant contribution to systemic lead concentrations once occupational exposure has ceased.

Pulmonary changes in glutathione (GSH) indicated by the concentration of non-protein sulphydryls showed a decrease of 43% in rats exposed for 5 h per day three times to 500 cm3/m3 (2100 mg/m3) styrene vapour. In these rats, only a marginal decrease was observed in the pulmonary cytochrome P450 oxidative metabolism. Following a single 24-h inhalation exposure to 500 cm3/m3 styrene, the decreases in GSH were 66% in lung but only 16% in liver. On the other hand, a multifold increase in the disposition of thioether compounds was found in urine. Pulmonary cytochrome P450-dependent metabolism was decreased, shown by low residual activities of 7-ethoxyresorufin (less than 20%), 7-ethoxycoumarin (53%) and 7-pentoxyresorufin O-dealkylases (76%). Epoxide hydrolase and GSH S-transferase enzyme activities which catalyze styrene detoxification were not decreased. Styrene exposure (24 h) of acetone-, phenobarbital- or 3-methylcholanthrene-pretreated rats resulted in pulmonary effects different from each other and from those of styrene alone. Acetone potentiated the lung effect and elevated 1.5-fold urine thioether output. Inducer pretreatment seemed to be a factor aggravating styrene toxicity; in effect this was clearest in acetone-induced rats. In general, GSH depletion accompanied by inhibition of cytochrome P450-dependent oxidative drug metabolism were the earliest biochemical lesions manifested in styrene-exposed lung.

Effects on health of cadmiumWHO approaches and conclusions A. Aitio & A. Tritscher International Programme on Chemical Safety, World Health Organization, Avenue Appia 20, CH-1211 Geneva 27, Switzerland (E-mail: aitioa@who.int)

Two workers exposed to trivalent chromium sulphate in a leather tannery had high concentrations of chromium in the urine. The concentration of chromium showed a workshift-related diurnal fluctuation, but it was remarkably high even after a vacation, indicating accumulation of chromium in the body. The concentrations of chromium in the workplace air, as collected on filters using standard techniques, were below 30 micrograms/m3. The chromium in the air was present in the form of large droplets not collected by the standard techniques. In the blood stream, chromium was transported exclusively in the plasma. No absorption of chromium through the skin could be detected. Absorption from the gastrointestinal tract was calculated to explain the findings.

Concentrations of toluene, tetrachloroethylene, and 1,1,1-trichloroethane were determined in blood collected from both forearms of subjects after one of their hands was soaked for 5 min in the corresponding solvent or in a thinner containing toluene, as a simulation of the washing of hands with solvent after work. The concentrations of toluene, tetrachloroethylene, and 1,1,1-trichloroethane on the soaked side were high, maximally 5.4, 9.0, and 4.0 mumol/l, respectively, and 20-, 130-, and 35-fold, respectively, compared to the contralateral side. Intraindividual differences were very marked, and dramatic changes were detected within a short period of time. It was not until after 3 h with toluene and 5 h with the chlorinated solvents that the difference between the two arms vanished. It is concluded that analyses of solvents in blood specimens drawn during or immediately after the workday may lead to markedly erroneous estimations of exposure.

1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was administered to rats to study its effects on the enzyme activities of the D-glucuronic acid pathway in the liver, small intestine and kidney. 2. The UDP-glucuronosyl transferase activity of male albino rats given TCDD (80 mug/kg, one dose, i.p.) 6 days before killing was significantly increased in all tissues examined, and UDP-glucuronic acid pyrophosphatase activity was markedly decreased in the liver. D-Glucuronolactone and L-gulonate dehydrogenase activities in the liver and small intestine were slightly decreased after TCDD treatment. 3. The activities of UDP-glucose dehydrogenase and beta-glucuronidase were unchanged. 4. The 24 h urinary excretion of L-ascorbic acid was enhanced 8-fold, although no difference was detected in the excretion of D-glucaric acid between the control and experimental animals. 5. These results suggest an increased capacity for glucuronide conjugation after treatment with TCDD. 6. The lack of increase in the urinary excretion of D-glucaric acid further challenges its use as a reliable indicator of enhanced drug metabolism. Xenobiotica

The excretion of chromium in the urine of workers exposed to chromium lignosulfonate was studied. The chromium in the dust was in the trivalent (III) oxidation state, and 30% of the particles were less than 5 micron in diameter. Chromium (III) lignosulfonate dust was rapidly absorbed, and a peak of urinary excretion was seen immediately after exposure. No appreciable accumulation of chromium occurred over 3 d, as evaluated by comparison with preshift urinary chromium concentrations. The addition of ethylenediaminetetra-acetate to the urine of exposed persons greatly enhanced the capacity of chromium to traverse a dialysis membrane; the same effect was seen with chromium (III) chloride. It is concluded that chromium (III) lignosulfonate yields chromium (III), which acts pharmacokinetically like water-soluble hexavalent chromium compounds.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (20 μg/kg) was administered to homozygous Gunn and Wistar as well as heterozygous rats, and the activity of UDP-glucuronosyltransferase determined in the liver and kidney toward o-aminophenol, p-nitrophenol, 4-methylumbelliferone, and bilirubin. Diethylnitrosamine was used to activate the enzyme in vitro. TCDD did not enhance UDP-glucuronosyltransferase (UDPGT) activity in the Gunn rat, either in the liver or in the kidney. In the Wistar rat, the UDPGT activity toward methylumbelliferone was enhanced eightfold in the liver and twofold in the kidney. TCDD did not affect UDPGT activity toward bilirubin. Diethylnitrosamine activated o-aminophenol and p-nitrophenol glucuronidation in vitro in the liver only. No activation in vitro due to diethylnitrosamine treatment could be seen in the liver of the TCDD-treated Wistar rat.

A head-space method for the simultaneous determination of benzene and toluene in blood using a gas chromatograph equipped with a photoionization detector was developed. Internal standards for benzene and toluene were fluorobenzene and o-xylene, respectively, and the detection limit was 5 nmol/l for both solvents. This method is sensitive enough for needs of biological monitoring of benzene and toluene in exposed workers. With automation it offers a possibility for routine measurements. An application of the method in monitoring exposed workers in the industry is presented.

Rats were exposed to 0, 75, 150 or 300 ppm (1 ppm = 1 cm3/m3 = 4.35 mg/m3) m-xylene for 24 h and then killed. In the lungs, the cytochrome P-450 decreased to 45, 13 and 20% of the control value with the increasing exposure intensity and the activity of 7-ethoxycoumarin O-deethylase to 70, 27 and 14%, respectively. The activity of epoxide hydrolase increased slightly after exposures both at 150 (1.6-fold) and 300 cm3/m3 (1.4-fold), while the other measured drug-metabolizing enzyme activities showed no consistent changes. The non-protein sulfhydryl group content of the lungs was not affected. The concentrations of m-xylene in blood indicated that the solvent uptake increased in the different exposure groups more than expected, based on atmospheric concentrations alone. Morphologic studies of the lungs with scanning electron microscopy showed no apparent changes after exposure to 300 cm3/m3 or after a high oral dose (2 ml/kg/day, 3 days). Inhalation exposure to m-xylene for 5 weeks (7 h/day, 4 days/week) at a concentration of 300 ppm lowered the contents of cytochrome P-450 in rat lungs to 65% and the activity of 7-ethoxycoumarin O-deethylase to 41% without any other marked effects on the other drug-metabolizing enzymes or on the levels of non-protein sulfhydryl groups. In this study, the selective destruction of cytochrome P-450 in rat lung could be shown both after acute and subacute exposures and at concentrations low enough to warrant occupational concern.