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The “totality” of the human exposure is conceived to encompass life-associated endogenous and exogenous aggregate exposures. Process-related contaminants (PRCs) are not only formed in foods by heat processing, but also occur endogenously in the organism as physiological components of energy metabolism, potentially also generated by the human microbiome. To arrive at a comprehensive risk assessment, it is necessary to understand the contribution of in vivo background occurrence as compared to the ingestion from exogenous sources. Hence, this review provides an overview of the knowledge on the contribution of endogenous exposure to the overall exposure to putative genotoxic food contaminants, namely ethanol, acetaldehyde, formaldehyde, acrylamide, acrolein, α,β-unsaturated alkenals, glycation compounds, N-nitroso compounds, ethylene oxide, furans, 2- and 3-MCPD, and glycidyl esters. The evidence discussed herein allows to conclude that endogenous formation of some contaminants appears to contribute substantially to the exposome. This is of critical importance for risk assessment in the cases where endogenous exposure is suspected to outweigh the exogenous one (e.g. formaldehyde and acrolein).

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated 2-naphthylamine [91-59-8], considering 2-naphthylamine in urine to characterise the internal exposure. Since the last evaluation of 2-naphthylamine, some new work has been published on the urinary excretion of 2-naphthylamine in occupationally non-exposed smokers and non-smokers. The literature added since the last evaluation also shows a heterogeneous data situation. Overall, the data situation on background exposure of occupationally non-exposed persons appears to be too heterogeneous and thus insufficient to evaluate a biological reference value (BAR) for 2-naphthylamine based on urinary excretion.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated 2-naphthylamine [91-59-8], considering 2-naphthylamine in urine to characterise the internal exposure. Since the last evalua-tion of 2-naphthylamine, some new work has been published on the urinary excretion of 2-naphthylamine in occupationally non-exposed smokers and non-smokers. The literature added since the last evaluation also shows a heterogeneous data situation. Overall, the data situation on background exposure of occupationally non-exposed persons appears to be too heterogeneous and thus insufficient to evaluate a biological reference value (BAR) for 2-naphthylamine based on urinary excretion.

EXCLI Journal;Vol. 17 2018

EXCLI Journal ; Vol. 8, 2009

Vinyl chloride is a human carcinogen. The characteristic tumour is the hepatic angiosarcoma, first observed in the 1970s in vinyl/polyvinyl chloride workers, especially in polymerization autoclave workers. Recent epidemiological studies demonstrate a dependence of the tumour incidence on both the duration and cumulative quantity of exposure. However, there is only limited data concerning the possible tumour latency times. Here, a case of hepatic angiosarcoma is presented that had been exposed to vinyl chloride in a very typical way as autoclave worker between 1957 and 1965. The patient was incidentally diagnosed with hepatic angiosarcoma in April 2008. Thus, the tumour latency time, from the beginning of occupational vinyl chloride exposure to clinical diagnosis, was 51 years. This underlines the importance of a continuing medical surveillance of workers exposed to vinyl chloride, at times before its carcinogenicity was recognized and regulatory action could be taken., EXCLI Journal ; Vol. 8, 2009

N­Acetyltransferase 2 (NAT2) genotyping may result in a considerable percentage in several ambiguous allele combinations. PHASE 2.1 is a statistical program which is designed to estimate the probability of different allele combinations. We have investigated haplotypes of 2088 subjects genotyped for NAT2 according to standard PCR/RFLP methods. In 856 out of 2088 cases the genotype was clearly defined by PCR/RFLP only. In many of the remaining cases the program clearly defined the most probable allele combination: In the case of *5A/*6C, *5B/*6A the probability for *5B/*6A is 99% whereas the alternative allele combination *5A/*6C can be neglected. Other combinations cannot be allocated with a comparable high probability. For example the allele combination *5A/*5C, *5B/*5D provides for *5A/*5C a probability of 69% whereas the estimation for *5B/*5D allele is only 31%. In the two most often observed constellations in our data [(*12A/*5B, *12C/*5C); (*12A/*6A, *12B/*6B, *4/*6C)] the probability of allele combination was ascertained as follows: *12A/*5B, 98%; *12C/*5C, 1.4% and *12A/*6A, 82%; *4/*6C, 17%; *12B/*6B, 0%. The estimation of the NAT2 haplotype is important because the assignment of the NAT2 alleles *12A, *12B or *13 as a rapid or slow genotype has been discussed controversially. Otherwise the classification of alleles in subjects which are not showing a clearly allocation can result in a rapid or slow acetylation state. This assignment has an important role in survey of bladder cancer cases in the scope of occupational exposure with aromatic amines.

N-Acetyltransferase 2 (NAT2) genotyping may result in a considerable percentage in several ambiguous allele combinations. PHASE 2.1 is a statistical program which is designed to estimate the probability of different allele combinations. We have investigated haplotypes of 2088 subjects genotyped for NAT2 according to standard PCR/RFLP methods. In 856 out of 2088 cases the genotype was clearly defined by PCR/RFLP only. In many of the remaining cases the program clearly defined the most probable allele combination: In the case of *5A/*6C, *5B/*6A the probability for *5B/*6A is 99% whereas the alternative allele combination *5A/*6C can be neglected. Other combinations cannot be allocated with a comparable high probability. For example the allele combination *5A/*5C, *5B/*5D provides for *5A/*5C a probability of 69% whereas the estimation for *5B/*5D allele is only 31%. In the two most often observed constellations in our data [(*12A/*5B, *12C/*5C); (*12A/*6A, *12B/*6B, *4/*6C)] the probability of allele combination was ascertained as follows: *12A/*5B, 98%; *12C/*5C, 1.4% and *12A/*6A, 82%; *4/*6C, 17%; *12B/*6B, 0%. The estimation of the NAT2 haplotype is important because the assignment of the NAT2 alleles *12A, *12B or *13 as a rapid or slow genotype has been discussed controversially. Otherwise the classification of alleles in subjects which are not showing a clearly allocation can result in a rapid or slow acetylation state. This assignment has an important role in survey of bladder cancer cases in the scope of occupational exposure with aromatic amines.

Problem: Cigarette smoking is the most important risk factor of transitional cell carcinoma of the urinary bladder. The effect of the glutathione S- transferases M1 (GSTM1) and M3 (GSTM3) on the influence of this risk factor was investigated. Methods: A total of 293 bladder cancer patients from Dortmund and Wittenberg as well as 176 surgical patients without any malignancy from Dortmund were genotyped for GSTM1 und GSTM3 according to standard PCR/RFLP methods. Smoking habits were also qualified by a standardized interview. Results: The percentage of GSTM1 negative cases was 63 % in the entire bladder cancer patient group compared to 50 % in the control group. GSTM3*A/*A genotype was 76 % in the entire group of bladder cancer cases and 74 % in controls. Smokers and ex-smokers were overrepresented in the bladder cancer patient group. A significant association between smoking status and GSTM1 or GSTM3 genotype could not be revealed. Conclusion: The elevated percentage of GSTM1 negative bladder cancer cases shows the important effect of this polymorphic enzyme on the development of bladder cancer. In contrast to some other studies, an influence of GSTM1 on the risk due to cigarette smoking could not be observed.

A recent clinical study has focused on: 1- the interaction between genetic variants of glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) and smoking on the risk of cardiovascular diseases, 2- the potential capacity of GSTM1 and T1 genotypes in modifying the effect of smoking on inflammation and endothelial function. In this study, we investigated whether carriage of these 2 polymorphisms altered the smoking impact on biological indices of inflammation and cellular adhesion. White blood cell count (WBC), albumin, C-reactive protein (CRP), interleukine-6 (IL-6), tumor necrosis factor-alpha (TNF-a), L-selectin, E-selectin, P-selectin and intracellular adhesion molecule-1 (ICAM-1) were measured in 189 non-smokers and 76 smokers (aged 20-55 years) genotyped for the GSTM1 and T1 polymorphisms. Accounting for age and sex, smokers lacking GSTM1 had a higher WBC count, CRP and ICAM-1 levels as compared to the other groups; interaction term between smoking and genotype being significant (p=0.05). Conversely, non-smokers lacking GSTM1 had a higher levels of TNF-a; the test for interaction being significant (p=0.05). No significant interaction was found between smoking and GSTT1 genotypes, considering the 9 biological indices. However, significantly lower levels of IL-6 were noticed for non-smokers with GSTT1-0 null allele (p=0.05). Our study confirms previous results showing that GSTM1 polymorphism could modulate the interrelationships between smoking and biological markers of inflammation and endothelial function., EXCLI Journal ; Vol. 3, 2004

The determination of toxicokinetic parameters is an essential component in the risk assessment of potential harmful chemicals. It is a key step to analyse the processes involved in the formation of DNA adducts which are connected with the development of chemical-induced cancer. A general problem is the extrapolation of toxicological data from experimental animals to the human organism. Therefore a valid characterisation of the relevant processes for the whole species is required, i.e., of population mean parameters instead of sets of parameters for different individuals. These, again, may vary between repeated experiments at the same or at different administered doses. Nevertheless, these differences are of great importance in obtaining a more precise insight into the variability structure of process investigated within the test animal population, so that a valid basis for further research is the final result. The theory of hierarchical models, particularly the work of Racine-Poon (1985) and Racine-Poon and Smith (1990), provides a procedure which incorporates both, modelling of the variability structure and estimation of population mean parameter vectors. The present study was designed to elucidate interindividual and interoccasion variability of toxicokinetic parameters relevant for the biological transformation of one of the basic petrochemical industrial compounds, ethylene (ethene), which is also a physiological body constituent, to its metabolite, ethylene oxide, which is a proven carcinogen.

The determination of toxicokinetic parameters is an essential component in the risk assessment of potential harmful chemicals. It is a key step to analyse the processes involved in the formation of DNA adducts which are connected with the development of chemical-induced cancer. A general problem is the extrapolation of toxicological data from experimental animals to the human organism. Therefore a valid characterisation of the relevant processes for the whole species is required, i.e., of population mean parameters instead of sets of parameters for different individuals. These, again, may vary between repeated experiments at the same or at different administered doses. Nevertheless, these differences are of great importance in obtaining a more precise insight into the variability structure of process investigated within the test animal population, so that a valid basis for further research is the final result. The theory of hierarchical models, particularly the work of Racine-Poon (1985) and Racine-Poon and Smith (1990), provides a procedure which incorporates both, modelling of the variability structure and estimation of population mean parameter vectors. The present study was designed to elucidate interindividual and interoccasion variability of toxicokinetic parameters relevant for the biological transformation of one of the basic petrochemical industrial compounds, ethylene 2 (ethene), which is also a physiological body constituent, to its metabolite, ethylene oxide, which is a proven carcinogen.

Toxikologische Wirkungen sogenannter "Xenoöstrogene" sind Gegenstand intensiver Diskussionen unter Fachleuten der Wissenschaft und in der Öffentlichkeit. Es besteht prinzipiell Einigkeit darüber, daß solche Stoffe in hohen Dosen in endokrine Regelkreise eingreifen können ("Potential"). Kontrovers diskutiert wird jedoch die Frage, welche Gefährdungen unter realistischen Expositionsszenarios von solchen Stoffen ausgehen ("Potenz"). In der in vivo-Situation ist für die relative biologische Wirksamkeit aufgenommener Stoffe neben deren Rezeptoraffinität ihre Toxikokinetik entscheidend. Um grundlegende toxikokinetische Parameter zu generieren, wurden zunächst analytische Verfahren zur Bestimmung der ausgewählten Xenoöstrogene in biologischem Material etabliert bzw. optimiert. In weiblichen DA/Han Ratten wurde nach Einmalgabe i.v. und p.o. die Toxikokinetik von p-tert-Octylphenol, Bisphenol A und Daidzein untersucht. Aus den Konzentrations-Zeit-Verläufen im Blut nach i.v.-Applikation wurden terminale Halbwertszeiten der Stoffe berechnet. Nach oraler Gabe unterschiedlich hoher Dosen wurden für alle Stoffe die Bioverfügbarkeiten bestimmt. Alle Blutspiegelkurven zeigen mehrgipflige Verläufe, die mit einer enterohepatischen Rezirkulation der Substanzen in Verbindung gebracht werden. Die Substanzen unterliegen alle einem ausgeprägten first-pass-Effekt und werden im Zuge des Phase-II-Metabolismus zu Glucuroniden und Sulfaten umgesetzt. Separate Experimente zeigen ferner, daß p-tert-Octylphenol und Daidzein bzw. deren Konjugate in erheblichem Umfang über die Galle ausgeschieden werden. Zusammenfassend läßt sich sagen, daß ausgehend von den im Rahmen des Verbundprojektes ermittelten toxikokinetischen Befunden und Literaturdaten für keinen der Prüfstoffe eine ausgeprägte Bioakkumulation zu erwarten ist.