Quantitative approaches for health risk assessment of environmental pollutants : estimation of differences in sensitivity, relative potencies, and margins of exposure

摘要

Historically, quantitative health risk assessment of chemical substances is based ondeterministic approaches. For a more realistic and informative health risk assessment, however,the variability and uncertainty inherent in measurements should be taken into consideration.The variability and uncertainty may be assessed by applying probabilistic methods whenperforming dose-response assessment, exposure assessment and risk characterization.The benchmark dose (BMD) method has been suggested as an alternative to the no observed(adverse) effect level (NO(A)EL) approach in dose-response assessment of non-cancer healtheffects. In contrast to the NO(A)EL that is limited to being one of the experimental dose levels,the BMD is estimated as the dose corresponding to a predetermined change in response,according to a model fitted to the dose-response data.In the present thesis, quantitative differences in sensitivity between dioxin sensitive Long-Evans (L-E) and dioxin resistant Han/Wistar (H/W) rats following long-term exposure to2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated. Sensitivity differences wereanalyzed by comparing BMDs for the two strains, considering a number of conventionaltoxicological endpoints, endpoints relevant for the endocrine system, and a group of boneparameters. Differences between the strains were most pronounced for hepatic foci; L-E ratswere approximately 20-40 times more sensitive than H/W rats. For body and organ weightparameters, L-E rats were 10-20 times more sensitive than H/W rats. For retinoid parametersand hepatic CYP1A1 induction, estimated differences between the strains were generallyabout 5-fold. For bone effects, significant strain differences were observed with the L-E ratbeing the most sensitive strain. This difference was most pronounced (about 49-fold) forcross-sectional area of proximal tibia. It was also concluded that the BMD approach is a moresuitable method for evaluation of bone parameters compare to the NOAEL approach. Inanother application, relative potency values (REPs) were established for a group of dioxinlike(DL) and non-dioxin-like (NDL) polychlorinated biphenyl (PCB) congeners as the ratiobetween BMDs, median effective doses (ED50s), or NOELs. This analysis was based onincreased liver weight, decreased hepatic vitamin A levels, and increased hepatic ERODactivity. The findings indicated that the BMD approach results in more reliable REP valuescompared to the ED50 and NOEL approaches. The BMD approach also provides moreinformation about the precision of the estimated REP values by the calculation of a two-sided90% confidence interval; a confidence interval may also be established for a ED50 ratio butnot for a NO(A)EL ratio. Overall findings in this analysis supported further development anduse of endpoint specific systems for assessment of human exposure to mixtures of chemicalswith similar as well as different mode-of-actions.Finally, the potential health impact of a group of PCBs was characterized by estimating thecumulative margins of exposure (MOEs) for the adult Swedish population. A cumulativeMOE distribution was quantified by simultaneous integration of a reference dose (RfD)distribution and a distribution for the human dietary exposure. Both a relative potency factor(RPF) based approach and an RPF-free approach were used for estimating the cumulativeMOE. Results indicated that the cumulative MOE could be up to four times lower for womencompared to men. The cumulative MOE reflected the MOE for PCB 126; other PCB congenershad little contribution. Compared to conventional MOE approaches, the newer approachesconsidered herein provide an improved tool under which potential health concerns can beassessed by accounting for both variability and various uncertainties, quantitatively,contributing to improving cumulative health risk assessments for the human population.