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H M Bolt

Publications and source records attributed to H M Bolt.

266 records · Page 15Linked to original sources
PubMedDate not supplied

Haemoglobin adducts of acrylonitrile and ethylene oxide in acrylonitrile workers, dependent on polymorphisms of the glutathione transferases GSTT1 and GSTM1.

Fifty-nine persons with industrial handling of low levels of acrylonitrile (AN) were studied. As part of a medical surveillance programme an extended haemoglobin adduct monitoring [N-(cyanoethyl)valine, CEV; N-(methyl)valine. MV: N-(hydroxyethyl)valine, HEV] was performed. Moreover, the genetic states of the polymorphic glutathione transferases GSTM1 and GSTT1 were assayed by polymerase chain reaction (PCR). Repetitive analyses of CEV and MV in subsequent years resulted in comparable values (means, 59.8 and 70.3 microg CEV/1 blood; 6.7 and 6.7 microg MV/1 blood). Hence, the industrial AN exposures were well below current official standards. Monitoring the haemoglobin adduct CEV appears as a suitable means of biomonitoring and medical surveillance under such exposure conditions. There was also no apparent correlation between the CEV and HEV or CEV and MV adduct levels. The MV and HEV values observed represented background levels, which apparently are not related to any occupational chemical exposure. There was no consistent effect of the genetic GSTM1 or GSTT1 state on CEV adduct levels induced by acrylonitrile exposure. Therefore, neither GSTM1 nor GSTT1 appears as a major AN metabolizing isoenzyme in humans. The low and physiological background levels of MV were also not influenced by the genetic GSTM1 state, but the MV adduct levels tended to be higher in GSTT1- individuals compared to GSTT1 + persons. With respect to the background levels of HEV adducts observed, there was no major influence of the GSTM1 state, but GST- individuals displayed adduct levels that were about 1/3 higher than those of GSTT1 + individuals. The coincidence with known differences in rates of background sister chromatid exchange between GSTT1- and GSTT1 + persons suggests that the lower ethylene oxide (EO) detoxification rate in GSTT1- persons, indicated by elevated blood protein hydroxyethyl adduct levels, leads to an increased genotoxic effect of the physiological EO background.

Acrylonitrile↗
PubMedDate not supplied

Toxicokinetics of p-tert-octylphenol in female DA/Han rats after single i.v. and oral application.

Female DA/Han rats were administered p-tert-octylphenol [OP; p-(1,1,3,3-tetramethylbutyl)-phenol], either intravenously (5 mg/kg body wt.) or orally by gavage (50 or 200 mg/kg body wt.). After i.v. administration the blood concentration-time curve of OP was fitted to a tri-exponential model, resulting in a final half-life (gamma-phase) of 36.1 h. This contrasts to much more rapid eliminations previously reported in male Wistar rats. The oral bioavailability of 50 mg/kg OP was 12.3% and of 200 mg/kg 8.4%. The higher dose (200 mg kg) was absorbed slower than the smaller dose, probably due to low solubility of OP in aqueous media. Maximal OP blood levels in female DA/Han rats receiving 50 and 200 mg OP/kg body wt, were 4.5 and 3 times higher than previously reported in male Wistar rats. The blood concentration-time curves after oral administration of OP to female DA/Han rats revealed pronounced interindividual differences, indicating extensive enterohepatic circulation of OP in this rat strain. In contrast to male Wistar rats, after application of high doses of OP to female DA/Han rats the compound was not completely eliminated within 48 h: under these conditions some bioaccumulation might therefore occur. The experimental toxicokinetics of OP appears as a relevant subject to be integrated into extrapolation of toxicological data, from in vitro to in vivo, and into systems of risk assessment of endocrine modulating activity which are currently being developed.

Administration, Oral↗
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Glutathione transferase alpha as a marker for tubular damage after trichloroethylene exposure.

To investigate possible persistent nephrotoxic effects of trichloroethylene (TRI), a retrospective study was carried out on 39 workers exposed to high levels of TRI from 1956 to 1975. Total protein levels in urine, as well as serum and urine creatinine and serum urea were unchanged in comparison with the control. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) was applied to differentiate between tubular and/or glomerular dysfunction. Urinary excretion of alpha-1-microglobulin and glutathione transferase (GST) alpha, as markers of proximal tubular damage, were correlated with the SDS-PAGE patterns of urinary proteins both in the TRI exposed and the control group. GST alpha was found in elevated concentrations in the urine of the TRI-exposed workers. No increase of urinary GST alpha was observed in the control group, even when alpha-1-microglobulin was elevated as a result of non-toxic damage. Both in the control and exposed groups, GST pi, a marker of distal tubular damage, was in the normal range. The results show that chronic exposure to high doses of TRI causes persistent changes to the proximal tubular system of the kidney and that GST alpha excretion into the urine is a marker well suited for quantitation of the extent of renal damage.

Biomarkers↗
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Psychological effects upon exposure to polyhalogenated dibenzodioxins and dibenzofurans.

Thirty workers who had been exposed to combustion products for several years due to testing of flame retarding qualities of building materials and 30 controls from the same facility were investigated. Concentrations found in samples taken from different places of the facility were up to 14,660 microg/kg for polybrominated dibenzofurans and up to 67.1 microg/kg for polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs). Physical examination, routine laboratory parameters, and blood fat concentrations of PCDDs and PCDFs revealed normal findings. Neurotoxic symptoms showed a weak tendency of overrepresentation among the exposed workers. The frequency of neurobehavioural symptoms increased significantly with trait anxiety independent of exposure to combustion products.

Adult↗
PubMedDate not supplied

Risk assessment of mixtures and standard setting: working towards practical compromises.

Basic concepts of 'dose/concentration additivity' and 'response addition/independence' may be applied to evaluate chemical mixtures in human toxicology, as well as in ecotoxicology. In the case of compounds that cause the same toxicological effect by the same mechanism, 'dose addition' is a more plausible form of joint action than 'response addition'. Data on the effects of halogenated hydrocarbons on the kidney, the effects of organic solvents on the central nervous system, and the effects of organophosphates on cholinesterase, are the basis of this assumption. For such compounds, response addition will generally underestimate risk. None the less, both dose addition and response addition are 'non-interactive' forms of joint action. As such, neither additivity assumption will accurately predict risk for compounds that exhibit toxicological interactions regardless of the primary mechanism(s) of toxicity. More often, the additivity approach overestimates the risk of a combination of chemicals. From a public health perspective, such results over-protect the public; hence this approach can be used for standard setting. The introduction of a special safety factor of 10 for the standard setting for mixtures in addition to those normally used for deriving acceptable daily intakes, reference doses or minimal risk levels is not supported by data. Instead, each exposure scenario should be considered on a case-by-case basis. Furthermore, considerations of multiple endpoints, including multiple organs, multiple effects, multiple mechanisms and potential interactions between such mechanisms, are very desirable for overall toxicity and risk assessment of chemical mixtures. In conclusion, additivity could be used to estimate potential risks for a combination of chemicals: only if scientific data support independence of effects can response independence be used as an alternative for standard setting.

Dose-Response Relationship, Drug↗
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Experimental designs and risk assessment in combination toxicology: panel discussion.

Advancing our knowledge on the toxicology of combined exposures to chemicals and implementation of this knowledge in guidelines for health risk assessment of such combined exposures are necessities dictated by the simple fact that humans are continuously exposed to a multitude of chemicals. A prerequisite for successful research and fruitful discussions on the toxicology of combined exposures (mixtures of chemicals) is the use of defined terminology implemented by an authoritative international body such as, for example, the International Union of Pure and Applied Chemistry (IUPAC) Toxicology Committee. The extreme complexity of mixture toxicology calls for new research methodologies to study interactive effects, taking into account limited resources. Of these methodologies, statistical designs and mathematical modelling of toxicokinetics and toxicodynamics seem to be most promising. Emphasis should be placed on low-dose modelling and experimental validation. The scientifically sound so-called bottom-up approach should be supplemented with more pragmatic approaches, focusing on selection of the most hazardous chemicals in a mixture and careful consideration of the mode of action and possible interactive effects of these chemicals. Pragmatic approaches may be of particular importance to study and evaluate complex mixtures; after identification of the 'top ten' (most risky) chemicals in the mixture they can be examined and evaluated as a defined (simple) chemical mixture. In setting exposure limits for individual chemicals, the use of an additional safety factor to compensate for potential increased risk due to simultaneous exposure to other chemicals, has no clear scientific justification. The use of such an additional factor is a political rather than a scientific choice.

Hazardous Substances↗
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Urothelial cancer of the bladder in an area of former coal, iron, and steel industries in Germany: a case-control study.

In a case-control study performed in an area of former coal, iron, and steel industries, the professional and lifestyle histories of 412 male urothelial bladder cancer inpatients (cases) and 414 inpatients with benign prostatic hyperplasia (controls) were investigated. Smoking habits were identified as the main confounder for occupational bladder cancer risk. Two hundred and forty (58.3%) of the bladder cancer inpatients and 146 (35.3%) of the inpatients with benign prostatic hyperplasia were smokers. The percentage of ex-smokers in the bladder cancer cases was 10.2%; the percentage of ex-smokers in the controls was 9.7%. Smoking-adjusted Mantel-Haenszel estimates of the odds ratios (OR&infMH;) for bladder cancer were elevated in underground hard-coal miners (OR&infMH; =2. 54, 95% CI =[1.64; 3.93]), chemical workers (OR&infMH; =2.16, 95% CI =[0.87; 5.38]), painters/varnishers (OR&infMH; = 2.42, 95% CI =[1. 05; 5.57]), technicians (OR&infMH; = 1.99, 95% CI =[0.95; 4.16]), and foundry workers (OR&infMH; = 2.22, 95% CI = [0.53; 9.08]). Administrative officers had significantly lower smoking-adjusted odds ratios (OR&infMH; = 0.61, 95% CI = [0.42; 0.88]). Although statistically not significant, the results of the Breslow-Day test of homogeneity of the odds ratios over the strata are compatible with interactions between tobacco smoking and the occupations of underground hard-coal miners (chi(2)&infBD; = 4.91, p=0.07) and chemical workers (chi(2)&infBR; = 3.32, p=0.06).

Adult↗
PubMedDate not supplied

European aspects of standard setting in occupational hygiene and medicine.

Occupational standards concerning the allowable concentrations of chemical compounds in the ambient air of workplaces have been established in several countries at national levels. With the integration of the European Union, a need exists for establishing harmonized Occupational Exposure Limits. For analytical developments, it is apparent that methods for speciation or fractionation of carcinogenic metal compounds will be of increasing practical importance for standard setting. Criteria of applicability under field conditions, cost-effectiveness, and robustness are practical driving forces for new developments. When the European Union issued a list of 62 chemical substances with Occupational Exposure Limits in 2000, 25 substances received a 'skin' notation. The latter indicates that toxicologically significant amounts may be taken up via the skin. Similar notations exist on national levels. For such substances, monitoring concentrations in ambient air will not be sufficient; biological monitoring strategies will gain further importance in the medical surveillance of workers who are exposed to such compounds. Proceedings in establishing legal frameworks for a biological monitoring of chemical exposures within Europe are paralleled by scientific advances in this field. A new aspect is the possibility of a differential adduct monitoring, using blood proteins of different half-life or lifespan. This technique allows differentiation between long-term mean exposure to reactive chemicals and short-term episodes, for example, by accidental overexposure. For further analytical developments, the following issues have been addressed as being particularly important: New dose monitoring strategies, sensitive and reliable methods for detection of DNA adducts, cytogenetic parameters in biological monitoring, methods to monitor exposure to sensitizing chemicals, and parameters for individual susceptibilities to chemical toxicants.

DNA Adducts↗
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Experimental pharmacokinetics and toxicology of acrylonitrile.

Pharmacokinetic experiments in rats and Rhesus monkeys show that inhaled acrylonitrile is nearly completely retained and metabolized. Metabolism, according to the literature, proceeds via direct reaction of acrylonitrile with biological sulfhydryl compounds and, to a much lesser extent, via glycidonitrile as a DNA-reactive oxidative metabolite. Clinical symptoms of acute acrylonitrile intoxication are in favour of an increased parasympathetic activity. This is confirmed by increased release of acetylcholine, in presence of acrylonitrile, from isolated chicken hearts of which the N. vagus is electrically stimulated. This explains an antidotal effect of atropine. The effectiveness of N-acetyl-cysteine as an acrylonitrile antidote may be explained by decreased alkylation and inactivation of acetylcholine-esterase.

Acrylonitrile↗
PubMedDate not supplied

Genetic and individual differences in the process of biotransformation and their relevance for occupational medicine.

Genetically determined differences in biotransformation of xenobiotics have been identified which are important for occupational medicine. This review highlights the following topics: (i) genetic polymorphisms in the activity of cholinesterases; (ii) polymorphisms in the cytochrome P-450 isozymes CYP2D6 and CYP2E1; (iii) polymorphisms in the N-acetyltransferase NAT-2; (iv) polymorphisms in the glutathione-S-transferases mu and theta. From the view-point of occupational medicine, these genetic polymorphisms may affect the toxicity of industrial and workplace chemicals, such as organophosphates (i), major solvents and monomers for plastics (ii), aromatic amines (iii), and compounds like styrene/styrene oxide, methyl halides, dichloromethane and ethylene oxide (iv). Individual differences in biotransformation linked with genetic polymorphisms also have a considerable influence on biological monitoring strategies and on human risk assessment.

Acetylation↗