Biomedical subjects

Hermann M Bolt

Publications and source records attributed to Hermann M Bolt.

9 recordsLinked to original sources

PubMed2002

Cytochrome P450 1B1, a new keystone in gene-environment interactions related to human head and neck cancer?

Alcohol consumption and tobacco smoking are major causes of head and neck cancers, and regional differences point to the importance of research into gene-environment interactions. Much interest has been focused on polymorphisms of CYP1A1 and of GSTM1 and GSTT1, but a number of studies have not demonstrated significant effects. This has mostly been ascribed to small sample sizes. In general, the impact of polymorphisms of metabolic enzymes appears inconsistent, with some reports of weak-to-moderate associations, and with others of no elevation of risks. The classical cytochrome P450 isoenzyme considered for metabolic activation of polycyclic aromatic hydrocarbons (PAH) is CYP1A1. A new member of the CYP1 family, CYP1B1, was cloned in 1994, currently representing the only member of the CYP1B subfamily. A number of single nucleotide polymorphisms of the CYP1B1 gene have been reported. The amino acid substitutions Val432Leu ( CYP1B1*3) and Asn453Ser ( CYP1B1*4), located in the heme binding domain of CYP1B1, appear as likely candidates to be linked with biological effects. CYP1B1 activates a wide range of PAH, aromatic and heterocyclic amines. Very recently, the CYP1B1 codon 432 polymorphism ( CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squamous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has pointed to interactive effects. This provides new molecular evidence that tobacco smoke-specific compounds relevant to head and neck carcinogenesis are metabolically activated through CYP1B1 and is consistent with a major pathogenetic relevance of PAH as ingredients of tobacco smoke.

Amino Acid Substitution↗

PubMed2002

Comparative assessment of endocrine modulators with oestrogenic activity. II. Persistent organochlorine pollutants.

Risk assessments of synthetic chemicals with oestrogen-like activity must take into account the high dietary levels of natural endocrine modulators in food. In view of current regulations of the European Union, a hygiene-based margin of safety (HBMOS) for xeno-oestrogens was defined as a quotient of estimated human daily intakes weighted by relative rodent in vivo potencies of the compounds. Such comparisons of intakes and potencies of natural isoflavones, with short half-lives, with those of polychlorinated organic pollutants (POP) displaying significant toxicokinetic accumulation, deserves the special consideration of toxicokinetics. For slowly accumulating compounds such comparison is much more favourable when based on comparative blood and tissue levels, not on scenarios of daily exposures. Observing these principles, the present communication extends the HBMOS concept to POP, using o,p'-DDT, the oestrogenic component of DDT mixtures, as a prototype. An HBMOS of 137 is derived for o,p'-DDT indicative of a sufficient margin of safety to ensure the absence of risk to human health due to its hormonal action, under exposure conditions now prevailing in Western countries.

Animals↗

PubMed2002

Is multiple chemical sensitivity a clinically defined entity?

In 1996 a WHO/IPCS Workshop has suggested to use as an appropriate descriptor of MCS the broader term "Idiopathic Environmental Intolerances (IEI)", in order to incorporate "a number of disorders sharing similar symptomatologies". Research was strongly encouraged. The following points have been put forward as a precondition to define MCS as a clinical entity: (a) establishment of diagnostic criteria, (b) identification of pathogenic mechanisms, together with, (c) an explanation of relationship between exposures and symptoms. Against this background, progress made in the fields of sensory physiology and neurobehaviour research must be debated. In particular, recent results on processing of cognitive stimuli have to be considered. IEI/MCS patients exhibited differences vs. controls in their reactions to intranasal challenge, consistent with changes in cognitive processing of suprathreshold chemosensory information. Trait anxiety and focus of attention have clearly been identified as major components in eliciting neurobehavioural MCS symptoms. Hence, the question as to whether MCS should be regarded as a clinically defined entity remains controversial, but important progress can be noticed in elucidating and defining the nature of this phenomenon, by a combined effort of several disciplines (toxicology and behavioural toxicology, psychology and psychophysiology, and clinical medicine). The new situation will call for a re-evaluation of traditional positions.

Cognition↗

PubMed2002

The enhanced bladder cancer susceptibility of NAT2 slow acetylators towards aromatic amines: a review considering ethnic differences.

Human bladder cancer may be caused by exposure to aromatic amines. The polymorphic enzyme N-acetyltransferase 2 (NAT2) is involved in the metabolism of these compounds. Two classical studies on chemical workers in Europe, exposed in the past to aromatic amines like benzidine, unambiguously showed that the slow acetylator status is a genetic risk factor for arylamine-induced bladder cancer. In the former benzidine industry in Huddington, Great Britain, 22 of 23 exposed cases with bladder cancer, but only 57% of 95 local controls without bladder cancer were of the slow acetylator phenotype. In Leverkusen, Germany, 82% of 92 benzidine-exposed chemical workers with bladder cancer were of the slow acetylator phenotype, whereas only 48% of 331 chemical workers who had worked at that plant were of the slow acetylator phenotype. This is in line with several smaller studies, which also show an over-representation of the slow acetylator status in formerly arylamine-exposed subjects with bladder cancer. Some of these studies included also subjects that were exposed to aromatic amines by having applied dyes, paints and varnishes. These European findings are in contrast to a large study on Chinese workers occupationally exposed to aromatic amines. In this study, only five of 38 bladder cancer cases occupationally exposed to arylamines were of the slow acetylator genotype. This is much lower than the ratio of slow acetylators to the general population in China. This points to different mechanisms of susceptibility for bladder cancer upon exposure to aromatic amines between European (Caucasian) and Chinese populations.

Amines↗

PubMed2002

Possible impact of human CYP2E1 polymorphisms on the metabolism of acrylonitrile.

Case reports of human accidental poisonings point to significant individual differences in human acrylonitrile metabolism and toxicity. A cohort of 59 persons with industrial handling of low levels of acrylonitrile has repetitively been studied from 1994 through 1999 as part of a medical surveillance programme. The analyses included adduct determinations of N-terminal N-(cyanoethyl)valine in haemoglobin and genotypings of the following cytochrome P-450 2E1 (CYP2E1) polymorphisms: G-1259C and C-1019T (two subjects heterozygous), A-316G (three subjects heterozygous), T-297A (15 subjects heterozygous), G-35T (eight subjects heterozygous), G4804A (two subjects heterozygous), T7668A (six subjects heterozygous). N-(Cyanoethyl)valine adduct levels were, if any, only slightly influenced by smoking and mainly determined by the external acrylonitrile exposures. The individual means and medians of N-(cyanoethyl)valine levels over the entire observation period were compared with the CYP2E1 variants (Wilcoxon rank sum test). No influences of the investigated CYP2E1 polymorphisms on the N-(cyanoethyl)valine levels appeared at the 5% level. However, there was a trend, at a level of P approximately 0.1, pointing to higher acrylonitrile-specific adduct levels in persons with the A-316G mutation. Higher adduct levels would be compatible with a slower CYP2E1-mediated metabolism of acrylonitrile and with lower extents of toxification to cyanide.

Acrylonitrile↗

PubMed2002

Estrogenic isoflavones in rodent diets.

Many rodent diets contain components such as soy isoflavones (daidzein and genistein) known to have estrogenic properties. The dietary background of phytoestrogens may modulate some responses to environmental estrogens when these compounds are tested in rodent bioassays. Thus, and since only few data were available on the phytoestrogen content of rodent diets commonly used in European laboratories, it was of interest to analyze the daidzein and genistein contents of our standard animal feeds. Isoflavone contents were determined in seven batches of rodent chow (from two suppliers in Germany, Altromin and Ssniff) by high-performance liquid chromatography, and also analyzed in six rodent diets from the United States. The soy-based rodent diets from Germany contained isoflavone (daidzein plus genistein) concentrations in the range of 0.3-0.55 mg/g feed. These isoflavone contents are similar to those analyzed in the US rodent diets, and similar to values reported by others, including one particular lot of feed (with 0.35 mg isoflavones per g) which produced a large uterotrophic response in immature ovariectomized rats [Environ. Health Perspect., 106 (1998) 369]. Coumestrol was found in a sample of commercial rabbit food at rather high levels (0.27 mg/g), but, this phytoestrogen was not detected (<1 microg/g feed) in any of the other samples we analyzed. The soy components in our rodent diet produce a measurable background of daidzein and genistein in blood of female DA/Han rats, total isoflavones (aglycone plus conjugates) ranging between 90 and 290 ng/ml plasma. The ovariectomized animals kept on this chow, showed no signs of estrogenization of the reproductive tract (uterus, vagina), and responded normally to (xeno-)estrogen administration in a uterotrophic assay [J. Steroid Biochem. Mol. Biol., 73 (2000) 1]. Moreover, ovariectomized Wistar rats on our standard rodent diet (Ssniff R/M H) had lower uterine weights than animals kept on the isoflavone-free (solvent extracted) chow; both groups of rats responded to genistein administration with an increase in uterine weights. These results suggest that--albeit the sensitivity of the rodent uterotrophic assay is not reduced by the use of a diet containing soy isoflavones at commonly encountered levels--attention should be given to a variable dietary phytoestrogen background.

Animal Feed↗

PubMed2002

Occupational versus environmental and lifestyle exposures of children and adolescents in the European Union.

There is recent international concern about specific exposures of children and adolescents to toxicants. In general, the situation within the European Union appears as follows. (i) OCCUPATIONAL EXPOSURE: Due to regulatory measures, there are almost no toxicologically significant occupational exposure situations of children to chemical toxicants. This contrasts to the situation in developing countries. There is also strict regulation of occupational exposure of adolescents (aged under 18). In consequence, the number of potentially exposed adolescents has been minimised. (ii) ENVIRONMENTAL EXPOSURE: Specific concern is directed towards exposures of infants, especially to neurotoxic heavy metals and carcinogens, and there is much regional differentiation of environmental exposures. (iii) FOOD: Recent research results are indicative of the general progress made in the field of food safety. (iv) INCIDENTAL ACUTE EXPOSURE: Besides drugs, household chemicals are a source of incidental acute intoxications in children. In Germany, there has been a particular focus on ingestion of lamp petroleum oils since 1989. (v) LIFESTYLE: Paramount problems are associated with increasing consumption of tobacco (mean age of starting smoking in Germany: 13.6 years), alcohol (percentage of addicts at ages 12-24 in Germany 6%) and cannabis among adolescents, calling for new ways of risk communication. In general, it will be necessary to consider children of different ages as separate risk groups.

Adolescent↗

PubMed2002

Integration of mechanistic data in the toxicological evaluation of endocrine modulators.

Controversy has arisen concerning the likelihood of adverse health effects due to exposure to hormonally active agents or endocrine modulators such as environmental estrogens. With the aim to improve the basis for their toxicological evaluation, several chemicals of anthropogenic (bisphenol A, octylphenol, o,p'-DDT) and of natural origin (daidzein, genistein) were investigated with regard to their mode of hormonal action and potency as well as toxicokinetics. Experimental toxicodynamic and toxicokinetic data illustrate important points in a comparative assessment of environmental estrogens. A novel concept, the Hygiene-Based Margine of Safety (HBMOS), has been suggested to characterize the relative impact of these potential endocrine modulators on human health: It integrates exposure scenarios (i.a. those generated within the European Existing Chemicals Programme) and in vivo rodent potency data for xenoestrogens and for dietary phytoestrogens. On the basis of these informations, HBMOS values calculated for the alkylphenol and bisphenol A appear sufficiently high to ensure the absence of a practical risk to human health under the present exposure conditions. For slowly accumulating compounds (e.g. DDT) with much longer half-lifes than isoflavones, such comparison should be based on comparative blood levels rather than on scenarios of daily exposures.

Animals↗

PubMed2002

Genetic susceptibility to environmental toxicants: the interface between human and experimental studies in the development of new toxicological concepts.

The growing knowledge of the genetic polymorphisms of enzymes metabolising xenobiotics in humans and their connections with individual susceptibility towards toxicants has created new and important interfaces between human epidemiology and experimental toxicology. The results of molecular epidemiological studies may provide new hypotheses and concepts, which call for experimental verification, and experimental concepts may obtain further proof by molecular epidemiological studies. If applied diligently, these possibilities may be combined to lead to new strategies of human-oriented toxicological research. This overview will present some outstanding examples for such strategies taken from the practically very important field of occupational toxicology. The main focus is placed on the effects of enzyme polymorphisms of the xenobiotic metabolism in association with the induction of bladder cancer and renal cell cancer after exposure to occupational chemicals. Also, smoking and induction of head and neck squamous cell cancer are considered.

Animals↗