| Endemic fluorosis caused by high fluoride exposure is one of the most serious environmental problems in China. The risk management of fluoride is very important to protect the people in endmic area. However, the environmental fluoride criteria of China adopting US EPA’ standand is unsuitable for controlling Chinese people exposure risk. In addition, the diagnostic indicator (dental fluorosis) is only a clinical one with less sensitivity of pathophysiological damage, and thus it is limited to diagnose the endemic fluorosis to some special people. Furthermore, both no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL), used to calculate the acceptable threshold for carcinogenic substance, have been employed for calculating non-carcinogen fluoride threshold. With the risk assessment mehod developing, benchmark dose (BMD) is thought as a more reasonable and scientific method than NOAEL or LOAEL given calculating the acceptable levels for fluoride with more precise ranging in 1% to 10%. Meanwhile, some bio-markers has been taken to assess the fluoride exposure risk, but most of them are used to describle pathological feature rather than benchmark research. Therefore, to establish the possible bio-indicator to take place the dental fluorosis, this research develops a new comprehensive bio-indicator based on the result of physiological and biochemical from an animal model.Ninety-six SD rats were selected and treated by gavage with NaF to establish the animal model. Rats had been treated with 0、2、4、8、16、320 mg/kg·bw, respectively for 3 months. In the process, the incidence of fluorosis was observed every other day. After 3 months, the conventional indicators, clinical indicators and key proteins were detected, and samples of rats’serum, bone and organs (heart, liver, spleens, lungs, kidneys, pancreas, thymus, submandibular gland and testicles or ovaries) were cryopreserved for tissue distribution levels analysis.Correlations between bio-indicators and exposure levels are found in our research (p<0.05), including bio-indicators BB2MG (white blood B2 microspheres), PIT (platelet count), ATF4 (activating transcription factor4), GLB/Ca (globulin/calcium) and TP/Ca (total protein/calcium). Among those indicators, BB2MG is one of the indicator reflecting renal health status and PIT for descring the condition of bone growth and development. Two indicators relating to liver function, ATF4 and GLB/Ca, are presented here along with TP/Ca representing the activation of hematopoietic function. Further function fitting analysis exhibits that R2 of bio-indicators mentioned above are around 0.7 but PIT is around 0.5. Moreover, results between tissue fluoride distribution and effects suggest that both BB2MG and GLB/Ca may related to the fluoride levels in serum and bone significantly (p<0.05), the similar trend is found between BB2MG and the fluoride content in pancreas, as well as GLB/Ca with lung. PIT has been confirmed its correlation with fluoride burden of serum, lung and sexual organ, and TP/Ca shows the similar trend to spleen, bone and pancreas. And the expression of ATF4 in serum is related to fluoride levels in bone and sexual organs (p<0.05). Considering the comprehensive damagment of fluoride exposure, indicators describled above are taken to develop the comprehensive indicator in our study, and applied to dedrive the RfD value for fluoride risk management. The result of RfD calculation indicates that the people oral RfD derived from the comprehensive indicator is 0.08 mg/(kg·d), which is lower than the value obtained from dental fluorosis (0.147 mg/(kgd)) and less than the value recommended by EPA (0.08 mg/(kg·d)). To minimize the risk of people health, the comprehensive bio-indicator would be better to apply in practical assessment than dental fluorosis. The comprehensive indicator developed in our study not only proveides the early and sensitive bio-markers, but also come up with a fundamental scientific idea for fluorosis prevention and treatment. |
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