Transient increase in micronucleus frequency and DNA effects in the comet assay in two patients after intoxication with 2,3,7,8-tetrachlorodibenzo- p-dioxin.

Abstract

The genotoxic effects in two patients with 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) intoxication were measured; an association with the workplace was suspected. We determined sister chromatid exchange (SCE), micronuclei (MN) and comet assay tail factor in peripheral lymphocytes of the patients and of control persons. A determination of polychlorinated dibenzo- p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) revealed almost pure TCDD at a concentration of 144,000 pg/g blood lipids in patient 1 and 26,000 pg/g blood lipids in patient 2, the first value being the highest level ever reported in humans. The source of TCDD ingestion remains unclear, since TCDD blood levels in 30 employees from the same workplace were in the normal range (1.2-8.6 pg/g blood lipids, average 3.0 pg/g), with the exception of three employees with moderately increased TCDD levels of 93, 149 and 856 pg/g blood lipids, who, however, did not show any clinical symptoms. Systematic measurements of air and equipment did not identify the source of TCDD. We determined SCE and MN in the peripheral lymphocytes of the patients and of control persons. A first determination, a few months after the manifestation of chloracne, showed normal values (2.4 and 2.5 MN/500 binucleated cells; 6.7 +/- 2.2 and 6.0 +/- 2.5 SCEs/metaphase) in both patients. Two months later, when TCDD levels were 85,600 pg/g blood lipids and 17,700 pg/g blood lipids, respectively, MN had increased enormously to 16 and 21.8/500 binucleated cells, SCE remained within normal range. One employee had a TCDD level of 856 pg/g blood lipids but did not develop any clinical symptoms or genotoxic effects, nor did three healthy employees with TCDD levels within background range (1.5-2.9 pg/g blood lipids). Within a period of 13 months, MN had returned to a nearly normal range in both patients. SCE had been within normal ranges all the time. We also determined the comet assay tail factor (DNA damage level) in peripheral lymphocytes of the patients. A first determination, when the TCDD level was 85,600 pg/g blood lipids (proband 1), showed an enormously high value of 33.5%. Nine months later, when the TCDD level was at 73,900 pg/g blood lipids, we found only a moderately increased value of 6.9%. Proband 2 did not have a significantly elevated comet assay tail factor, neither at the TCDD level of 17,700 pg/g blood lipids nor at the level of 15,700 pg/g blood lipids. This delayed and transient effect seems to indicate some kind of "indirect" or "secondary" genotoxic effect of TCDD. However, DNA damaging effects, caused directly or indirectly, could be an indicator for a possible carcinogenic risk of TCDD.