Dioxins such as TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) are persistent and ubiquitous environmental poisons which are extremely toxic to many animal species. Human risks of dioxin exposure are controversial. This is exemplified by the fact that the maximal tolerable daily intake level (TDI) calculated by U.S.EPA is three orders of magnitude lower than those calculated in Western Europe or Canada. Since many foodstuffs contain low concentrations of dioxins (fish, dairy products, meat) the adopted TDI level is crucial for economic life. In fact the American TDI, literally enforced, would render both Baltic fish and central European milk largely inedible. This illustrates that a reliable risk evaluation of these compounds is crucial to guarantee at the same time the safety of consumers, and the confidence for producers that only scientifically sound decisions are enforced.
In this proposal a more accurate risk evaluation is aimed at by combining epidemiological data with selected toxicological results, in order to narrow down the margin of uncertainty. The end points selected are cancer and developmental defects which are considered the most relevant and sensitive potential health consequences of dioxin.
In rodent bioassay both induced and uninduced tumorigenicity is assessed by analysing preneoplastic foci in the liver. Essentials of the work are constructing a wide dose-response relationship to improve extrapolation, and comparing the sensitivity between different rat strains which are differently sensitive to the acute toxicity of TCDD (over 1000-fold difference). Such differences between species and strains add remarkably to the uncertainty of species extrapolation, and it is not known as yet, if there is also a difference in tumorigenic potency. These dose-response results will be compared with results on soft tissue sarcoma which will be analysed in a case-control study correlating this cancer with dioxin concentrations in fat tissue.
Dental defects have been selected as endpoints of developmental toxicity on basis of preliminary information. Dental defects in the permanent first molars (mineralized during the first two years of life) will be compared with the dioxin exposure of the child during nursing. In animal studies the dose-response of dioxin exposure will be investigated.
According to our preliminary calculations this combined epidemiological/toxicological approach can be used to compare doseresponse relationships of dioxins regarding various toxic endpoints, and to evaluate the likelihood of similar dose-responses in animals and man. It can also be used to illustrate the most likely endpoints at the present environmental dioxin levels. The approach is to our knowledge also the first attempt to directly incorporate epidemiological and toxicological data from the same project to test the animal-human extrapolation.
Funding SchemeCSC - Cost-sharing contracts
171 77 Stockholm
171 77 Stockholm