Organohalogen environmental pollutants in Baltic fish : Chemical charcterization and toxicological evaluation with a focus on bone disturbances

Sammanfattning: The present study was initiated due to concern about toxicological consequences associated with the exposure to persistent organic pollutants (POPs) via the consumption of Baltic fish. In Sweden, fish from the Baltic Sea is a major dietary source of POPs but also an important source of essential nutrients. Balancing risks and benefits of fish consumption is an important public health topic. Most cases of environmental contamination result in exposure to a mixture of chemicals and evaluating the potential hazards following this exposure is a challenge because effects are influenced by multiple factors that may have totally independent actions but also exhibit additive, synergistic or antagonistic effects. The overall aim was to identify any adverse effects, with special emphasis on bone effects, of long-term low dose exposure to a mixture of POPs, present in Baltic fish, to link the observed effects to particular organohalogens or to dietary factors, and to identify the bone parameters and/or skeletal sites most sensitive to dioxin exposure. The chosen strategy was to fractionate and separate POPs derived from Baltic herring (Clupea harengus) in order to obtain herring oil fractions with differing proportions of organohalogen pollutants and to perform a traditional subchronic toxicity study in female rats at dose levels, corresponding to 8, 40 and 160 times the estimated human intake of fish in the Swedish population. The fractionation of herring oil resulted in substantial reduction of most of the pollutants in the triacyIglycerol fraction and a pronounced enrichment of most of the pollutants into the two other fractions. Polychlorinated biphenyls (PCB) and 1, 1, 1 -tri chloro-2,2-bis(4-chlorophenyl)ethane (DDT) were the most abundant pollutants in Baltic herring during the mid-1990s. Polyclorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) showed a higher liver retention than other contaminants. The toxicological examination showed that exposure to Baltic herring oil at dose levels, corresponding to human intake of 1.6, 8.2 or 34.4 kg fish /week resulted in general toxic effects that could be described as minimal, even at the high dose level. The spectrum of toxic effects was similar to low-dose effects of exposure to dioxinlike pollutants. Because of the complex nature of the mixture, the effects could not be conclusively linked to a specific contaminant. Clear differences in bone geometry and density were observed in rats exposed to the different diets. The obtained results were put in the context of a simultaneous exposure to various nutritional factors, such as polyunsaturated fatty acids (PUFA), vitamin A and D. However, the changes could not be linked to any isolated chemical pollutant or nutrient, suggesting synergistic or antagonistic effects of several components of the diets. Serum levels of n-6 and n-3 PUFA reflected the vegetable oil or fish oil content of the diets. By using Han/Wistar (H/W) and Long-Evans (L-E) rat strains, which differ in their sensitivity to the toxicity of Aryl hydrocarbon receptor (AhR) ligands, we further clarified the role of AhR and quantified the most sensitive endpoints in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced bone toxicity. We performed more extensive studies of load-bearing skeletal sites to identify the bone parameters and skeletal sites most sensitive to dioxin-induced AhR-mediated bone toxicity. Long bones were consistently more sensitive to dioxin exposure than lumbar vertebra, which could be the result of differences in bone resorption and/or bone formation rates in different types of bones. The most sensitive parameter for dioxin-induced bone toxicity was the cross-sectional area of femoral metaphysis. Untreated H/W rats with structurally aberrant AhR exhibited shorter femur and lumbar vertebra and consistently thinner, denser and more fragile bones than L-E rats with normal AhR structure, which provide important information on a possible role of AhR in bone biology. A 10 to 100-fold difference in sensitivity to dioxin-induced bone effects between L-E and H/W rats were observed in this study, supporting a distinct role for AhR in dioxin-induced bone abnormalities.