Discontinuity in the cancer slope factor as it passes from high to low exposure levels--arsenic in the BFD-endemic area.

BACKGROUND: The ingestion of inorganic arsenic causes bladder and lung cancers demonstrably at >400-500ug/L but questionably below 100-200ug/L. Using the standard 42-village cancer mortality dataset from the Blackfoot-disease (BFD) endemic area of southwest Taiwan (Wu et al., 1989), we examined the risk from low exposures by excluding the high exposures. METHOD: Poisson regression analyses with the sequential removal of the highest exposure village have been performed using the median, mean, or maximum village well water arsenic level and demonstrated graphically. RESULTS: Risk estimates are positive when villages with exposures of 200-400ug/L are included and significantly so when villages with >400ug/L are included. Risk estimates for exposures below 100ug/L are negative but rarely significantly so. The inflection point where the slope is no longer positive occurs in the range of 100-200ug/L, depending upon whether the exposure metric used is the median, the mean or the maximum. CONCLUSION: There is a discontinuity in the cancer slope factor or risk from arsenic exposure that occurs in the range of 100-200ug/L. Above these levels, there are significantly positive risks, while below these levels there are not. The analysis reveals within this dataset an intrinsic non-linearity in the cancer risk. The literature speaks to this discontinuity, but this is the first demonstration within a single dataset that shows the discontinuity across the full exposure range and where the low-dose data are not compromised with high-dose data.

Association of serum α-tocopherol with sex steroid hormones and interactions with smoking: implications for prostate cancer risk.

BACKGROUND: Vitamin E may protect against prostate cancer, possibly only in smokers and, we hypothesize, through altered sex steroid hormones. A controlled trial in smokers showed that sex hormone levels were inversely associated with baseline serum α-tocopherol and decreased in response to vitamin E supplementation. The vitamin E-hormone relation is understudied in non-smokers. METHODS: Serum sex steroid hormones and α-tocopherol were measured for 1,457 men in NHANES III. Multivariable-adjusted geometric mean hormone concentrations by α-tocopherol quintile were estimated. RESULTS: We observed lower mean testosterone, estradiol, and SHBG concentrations with increasing serum α-tocopherol (Q1 = 5.5 and Q5 = 4.6 ng/ml, p-trend = 0.0007; Q1 = 37.8 and Q5 = 33.1 pg/ml, p-trend = 0.02; Q1 = 38.8 and Q5 = 30.6 pg/ml, p-trend = 0.05, respectively). Interactions between serum α-tocopherol and exposure to cigarette smoke for total testosterone, total estradiol, and SHBG were found with the inverse relation observed only among smokers. CONCLUSIONS: Results from this nationally representative, cross-sectional study indicate an inverse association between serum α-tocopherol and circulating testosterone, estradiol, and SHBG, but only in men who smoked. Our findings support vitamin E selectively influencing sex hormones in smokers and afford possible mechanisms through which vitamin E may impact prostate cancer risk.

Bladder cancer and arsenic exposure: differences in the two populations enrolled in a study in southwest Taiwan.

OBJECTIVE: Analyses of bladder cancer mortality in the Black Foot Disease (BFD) endemic area of southwest Taiwan conducted by Morales et al. showed a discontinuity in risk at 400 microg/L arsenic in the drinking water in a stratified analysis and no discontinuity in a continuous analysis. As the continuous analysis presentation had been used by both the NRC and the EPA to assess the carcinogenic risk from arsenic ingestion, an explanation of the discontinuity was sought. METHODS: Review of 40 years of published health studies of the BFD-endemic area of SW Taiwan showed that earlier publications had limited their cancer associations with arsenic levels in artesian well waters and that the reports of Morales et al., NRC, and EPA failed to do so. Underlying data for the Morales et al. study were obtained from the appendix to the NRC report. Bladder cancer mortality rates were calculated from case counts and person-years of observation for each study village. Villages were categorized by water source according to the descriptions from the underlying study. Graphic and regression analyses were conducted of the bladder cancer mortality rates using exposure as a continuous variable and simultaneously stratifying by water source. RESULTS: The median village well arsenic levels ranged from 350 to 934 microg/L for villages solely dependent on artesian well water and from 10 to 717 microg/L for villages not solely dependent on artesian well water. Bladder cancer mortality rates were found to be dependent upon the arsenic level only for those villages that were solely dependent on artesian well water for their water source. Bladder cancer mortality rates were found to be independent of arsenic level for villages with non-artesian well water sources. CONCLUSIONS: The data indicate that arsenic exposure levels do not explain the bladder cancer mortality risk in SW Taiwan among villages not dependent upon artesian well water. The association for villages dependent upon artesian well water may be explained either by arsenic acting as a high-dose carcinogen or in artesian well water as a co-carcinogen with some other aspect of artesian well water (possibly humic acid). Arsenic exposure level alone appears to be an insufficient exposure measure to describe the risk of bladder cancer mortality in the BFD-endemic area. Risk analyses that fail to take water source into account are likely to misrepresent the risk characterization, particularly at low arsenic levels.