Changes to classifying carcinogens.

BACKGROUND: In 1997, the International Agency for Research on Cancer classified 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a group 1 human carcinogen, based largely on four highly exposed industrial cohorts that showed an excess of all cancers combined. In this study, we extended the follow-up period for the largest of these cohorts by 6 years and developed a job-exposure matrix. METHODS: We did cohort mortality analyses involving 5132 chemical workers at 12 U.S. plants by use of life table techniques (U.S. population referent) and Cox regression (internal referent). We conducted exposure-response analyses for 69% of the cohort with adequate work history data and adequate plant data on TCDD contamination. All P values are two-sided. RESULTS: The standardized mortality ratio (SMR) for all cancers combined was 1.13 (95% confidence interval = 1.02-1.25). We found statistically significant positive linear trends in SMRs with increasing exposure for all cancers combined and for lung cancer. The SMR for all cancers combined for the highest exposure group was 1.60 (95% confidence interval = 1.15-1.82). SMRs for heart disease showed a weak increasing trend with higher exposure (P = .14). Diabetes (any mention on the death certificate) showed a negative exposure-response trend. Internal analyses with Cox regression found statistically significant trends for cancer (15-year lag time) and heart disease (no lag). CONCLUSIONS: Our analyses suggest that high TCDD exposure results in an excess of all cancers combined, without any marked specificity. However, excess cancer was limited to the highest exposed workers, with exposures that were likely to have been 100-1000 times higher than those experienced by the general population and similar to the TCDD levels used in animal studies.

Carcinogens↗

PubMed1999

DNA repair in primary human keratinocyte cultures after low level exposure to bis(2-chloroethyl)sulfide.

The literature has reported the appearance and disappearance of single-strand breaks (SSBs) in the DNA of rat keratinocytes after exposure to low levels of bis(2-chloroethyl) sulfide (BCES). Since SSBs are a consequence of depurination or depyrimidination followed by excision of the apurinic or apyrimidinic site and deoxyguanosine (GdR) is the major alkylation site in DNA exposed to BCES, it was hypothesized that repair occurred by a GdR-specific base replacement and not by large section repair. To test this hypothesis, cultures of human keratinocytes (HK) were preincubated with 5-bromo-2'-deoxyuridine (BUdR), a heavy analog of thymidine (TdR) incorporated into replicating DNA, immediately before exposure to BCES. Cultures were incubated postexposure with BUdR, radiolabeled GdR, and/or deoxyadenosine (AdR), to measure base-specific repair, and/or radiolabeled TdR, to measure DNA replication and large section repair. A CsCl density gradient was used to remove any BUdR-containing postexposure DNA replication. Each gradient was assayed for radioactivity (cpm) and DNA content (absorbance at 260 nm). The peak A260 fractions were pooled and rebanded in another CsCl gradient. If DNA repair had occurred, the specific activity (cpm/A260) of the peak A260 fraction in the gradient would be greater than control. After exposure of the cultures to BCES, there was a concentration-dependent increase in the specific activity for [3H]GdR but not [4C]TdR over the concentration range used (20-50 microM BCES). A concentration-dependent increase in specific activity was also detected after [14C]AdR exposure. The literature has also reported that the removal of damaged DNA bases after alkylation is via glycosylases. In this series of experiments, we have demonstrated that cultures of HK exposed to the alkylating agent BCES repair their damaged DNA by the replacement of the damaged base only. In the case of BCES exposure, it is the GdR base and to a lesser extent the AdR base.

Carcinogens↗