A Case-control Study On The Relationship Between Polybrominated Diphenyl Ethers,Heavy Metals And The Risk Of Thyroid Cancer

Objective Polybrominated Diphenyl Ethers（PBDEs）,Cadmium（Cd）,Lead（Pb）,Arsenic（As）,Mercury（Hg）are ubiquitous environmental endocrine disruptions in the environment with strong biological toxicity,can disrupt normal thyroid function.This study aims to understand the exposure levels of PBDEs,Cd,Pb,As and Hg in thyroid cancer patients（TC）in Anhui Province,and to explore the association between their individual exposure and combined exposure and the risk of TC.Methods From December 2017 to March 2019,new diagnosed TC patients were collected at Anhui Provincial Cancer Hospital as case group.1: 1 matched healthy residents in the community were collected as control group,according to gender and age（± 3 years）.After obtaining the informed consent of the subjects,a questionnaire survey was conducted.The questionnaire content includes social demographic characteristics,behavioral habits,medical radiation exposure history,disease history,family history of disease,etc.Fasting anticoagulant and morning urine specimens were collected in the next day.The concentrations of nine PBDEs congeners in plasma were determined by gas chromatography-mass spectrometry.Automatic biochemical analyzer was used to determine the triglyceride and total cholesterol concentrations in plasma,and the total lipid was calculated according the formula to correct the PBDEs concentrations.Cd in the urine was measured by atomic absorption spectrometer,while Pb,As and Hg in the urine were measured by an inductively coupled plasma emission spectrometer.The concentration of creatinine in the urine was measured by an ultraviolet spectrophotometer to correct the concentration of metals elements.According to the tertiles of each test substance exposure level in the control group,all the subjects were divided into three exposure levels: low exposure,medium exposure,and high exposure level.Multivariate logistic regression models were used to explore the relationships between PBDEs exposure,4 heavy metals individual and combined exposure level,and the TC risk and pathplogical characteristics.Multivariate unconditional logistic regression model was used to analyze the multiplicative terms of PBDEs and heavy metals on the risk of TC.Relative excess risk due to interaction（RERI）,attributable proportion due to interaction（AP）,and synergy index（S）were used to evaluate the additive interaction of PBDEs and heavy metals on the risk of TC.Results A total of 308 TC cases and 308 health control were collected.Gender ratio of male to female was 1: 2.89.The average age of the cases was 44.73 years,and that of the controls was 46.10 years.After adjusted for total lipid,the concentrations of BDE-028,BDE-047,BDE-099,BDE-183,BDE-209,Σ₇PBDE,Σ₈PBDE were higher in the cases than in the controls.The concentrations of BDE-100,BDE-153 and BDE-154 were not significantly different between the two groups.Compared with the low exposure level,high exposure level of BDE-028,BDE-209,Σ₇PBDE,and Σ₈PBDE increased 196%,67%,83%,and 91% TC risk respectively（OR=2.96,95% CI: 1.72-5.09;OR=1.67,95%CI: 1.03-2.69;OR=1.83,95%CI: 1.68-4.75;OR=1.91,95%CI: 1.17-3.14,respectively）,and medium exposure level and high exposure level of BDE-047,BDE-099,and BDE-183 were all related to the increased risk of TC（BDE-047 medium exposure vs low exposure: OR =2.15,95%CI: 1.22-3.77,high exposure vs low exposure OR =4.16,95%CI: 2.35-7.36;BDE-099 medium exposure vs low exposure: OR =3.52,95%CI: 1.84-6.71,high exposure vs low exposure OR =5.16,95%CI: 2.82-9.45;BDE-183 medium exposure vs low exposure: OR=1.93,95%CI: 1.04-3.60,high exposure vs low exposure OR =4.58,95%CI: 2.59-8.11）.Some PBDEs homologues were associated with TC risk of different pathological features.Among these PBDEs homologues,the exposure level of BDE-209 was correlated with the risk of TC with tumor diameter ≤1.0 cm,no lymph node metastasis,and 1 stage of AJCC.The exposure levels of BDE-153 and BDE-209 were related to the pathological characteristics of thyroid cancer patients such as tumor diameter and lymph node metastasis.After adjusted for creatinine,the geometric mean of Cd,Pb,As and Hg were: 0.93 μg/g,25.16 μg/g,30.79 μg/g,and 16.02 μg/g in the case group,and 0.74 μg/g,12.76 μg/g,13.22 μg/g and 8.06 μg/g in the control group.The multivariate conditional logistic regression results showed that,both As and Hg exposure level were positively correlated with the risk of TC.Compared with low exposure,the medium exposure level of As increased the TC risk by 230%（OR = 3.30,95% CI: 1.70-6.40）,and high exposure level of As increased the TC risk by 294%（OR = 3.94,95% CI: 2.03-7.65）.The high exposure level of Hg increased the risk of TC by 140%（OR = 2.40,95% CI: 1.35-4.26）.The combined exposure of the four heavy metals also increased the risk of TC（medium exposure vs low exposure: OR =1.93,95%CI: 1.07-3.51;high exposure vs low exposure: OR =2.95,95%CI: 1.46-5.97,respectively）,this association was also found in female populations（high exposure vs low exposure: OR =2.51,95%CI: 1.11-5.68）.The levels of As,Hg and four heavy metals combined exposure were associated with the risk of TC in multiple different of pathological features.But the high exposure level of Pb was only related to the increased risk of TC with extra-thyroidal extension invasion and 2-4 stages of AJCC,with an increase of 90% and 227% respectively.Correlation analysis between heavy metals and pathological characteristics of TC patients showed that patients with high exposure level of As were more likely to have no lymph node metastasis（OR = 0.48,95% CI: 0.23-0.98）.The interaction analysis results showed that when BDE-209 and Pb were co-exposed,the multiplicative and additive interactions were statistically significant,showing an antagonistic effect on the risk of TC(OR_int=0.31,95%CI: 0.15-0.66,RERI=-2.14,95%CI:-4.24^-0.03,S=0.40,95%CI: 0.20-0.81).The combined exposure of BDE-183 and As had an additive interaction on the risk of TC,showing a synergistic effect（RERI=2.48,95%CI: 0.59-4.36;AP=0.52,95%CI: 0.27-0.77;S=2.97,95%CI: 1.09-8.05）.When BDE-028,BDE-047,BDE-099,and BDE-209 were co-exposed with Hg,there were synergistic effects on TC risk(BDE-028 and Hg: OR_int = 3.17,95% CI: 1.49-6.78,RERI = 2.75,95% CI: 1.12-4.39,AP = 0.69,95% CI: 0.48-0.90;BDE-047 and Hg: OR_int = 2.58,95% CI: 1.19-5.59,RERI = 2.47,95% CI: 0.88-4.08,AP = 0.63,95 % CI: 0.40-0.87;BDE-099 and Hg: AP = 0.40,95% CI: 0.11-0.68,S=1.87,95% CI: 1.01-3.46;BDE-209 and Hg: OR_int = 3.67,95% CI: 1.72-7.83,RERI = 2.05,95% CI: 0.85-3.25,AP = 0.73,95% CI: 0.49-0.97).But the co-exposure of BDE-183 and Hg showed an antagonistic effect on TC risk(OR_int = 0.34,95% CI: 0.16-0.75).Conclusion The exposure levels of some PBDEs congeners are associated with the risk of TC and the pathological characteristics of TC patients.Among them,the high exposure level of BDE-209 is related to the increased risk of TC with less aggressive tumors.As the exposure levels of As and Hg increase,the risk of TC increases.The exposure level of As is related to the characteristics of lymph node metastasis in TC patients.The combined exposure of four heavy metals is also related to the increased risk of TC.There are interaction effects between some PBDEs congeners and Pb,As,Hg on the risk of TC.