Current developments in toxicological research on arsenic

There is a plethora of recent publications on all aspects relevant to the toxicology of arsenic (As). Over centuries exposures to arsenic continue to be a major public health problem in many countries. In particular, the occurrence of high As concentrations in groundwater of Southeast Asia receives now much attention. Therefore, arsenic is a high-priority matter for toxicological research. Key exposure to As are (traditional) medicines, combustion of As-rich coal, presence of As in groundwater, and pollution due to mining activities. As-induced cardiovascular disorders and carcinogenesis present themselves as a major research focus. The high priority of this issue is now recognized politically in a number of countries, research funds have been made available. Also experimental research on toxicokinetics and toxicodynamics and on modes of toxic action is moving very rapidly. The matter is of high regulatory concern, and effective preventive measures are required in a number of countries

Extremely long latency time of hepatic angiosarcoma in a vinyl chloride autoclave worker

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

The influence of glutathione S-transferases M1 and M3 on the development of bladder cancer

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. --Bladder cancer,glutathione S-transferase M1,glutathione S-transferase M3,smoking

Estimation of N-acetyltransferase 2 haplotypes

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. --PHASE 2.1,NAT2 genotyping,single nucleotide polymorphism

Novi aspekti u klasifikaciji kancerogena

The existing systems of classification of carcinogens should include a distinction between genotoxic and non-genotoxic chemicals. For non-genotoxic chemicals, permissible exposure levels can be derived at which no relevant human cancer risks are anticipated. While genotoxic carcinogens can induce chromosomal effects without mutagenic action, non-DNA-reactive genotoxins affecting topoisomerase or the spindle, or those having an exclusively aneugenic effect can be carcinogenic only at high, toxic doses. Specific mechanisms of clastogenicity and processes of carcinogenesis based on reactive oxygen have practical thresholds. Since reactive oxygen species (ROS) are generally genotoxic, the question is whether chemicals that increase ROS production will add to endogenously produced background levels and lead to nonlinear dose-effect relationships. Taking into account the presence of endogenous carcinogens, it is now becoming evident that carcinogenic risk extrapolation to low doses must be considered according to the mode of action.U postojećem sistemu klasifikacije kancerogenih tvari utvrđena je razlika između genotoksičnih i negenotoksičnih kemikalija. Za negenotoksične kemikallije mogu se izvesti pretpostavljeni stupnjevi izlaganja kod kojih ne postoji značajan rizik od pojave raka kod ljudi. Za genotoksične kancerogene mogući su na primjer inducirani kromosomski efekti bez početka procesa mutageneze, dok genotoksični toksini koji se ne vežu za DNA-molekulu, a djeluju na topoizomere ili diobeno vreteno ili su aneugeni, izazivaju kancerogene efekte jedino u visokim, toksičnim dozama. Za specifične mehanizme klastrogenog djelovanja i procesa kancerogeneze koji se baziraju na reaktivnom kisiku postoji prag početka procesa. Kako su vrste kemikalija reaktivne na kisik (ROS) u načelu genotoksične, pojavljuju se pitanja da li kemikalije koje povećavaju produkciju ROS-vrsta treba pridodati endogenim kancerogenima pozadinskog stupnja koji uzrokuju nelinearni odnos doze i učinka. Uzimajući u obzir rasprave o prisutnosti endogenih kancerogena, sada postaje jasno da se kancerogeni rizik od niskih doza mora uzeti u obzir sukladno načinu njihova djelovanja

Estimation of N-­acetyltransferase 2 haplotypes

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