Associations Between PCDD/Fs Exposure And Lung Function Levels Among Foundry Workers And General Residents

PCDD/Fs(Polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans),commonly referred to as “dioxins”,are ubiquitous persistent organic pollutants.Metallurgical industry is the main source of PCDD/Fs in China.PCDD/Fs from combustion processes in industrial production will contaminate the air in the workshop,being inhaled by the workers.Meanwhile,when PCDD/Fs are discharged from the industrial sources,they will undergo long-term and long-range transport via air masses,and can bioaccumulate via food chain,entering human body through digestive tract.Numerous toxicological studies have discovered that the lung has been confirmed to be a target organ for PCDD/Fs.Many cohort studies have also associated PCDD/Fs exposure with an increased incidence of chronic obstructive pulmonary disease(COPD)and lung cancer.However,almost all existing epidemiologic researches focused on heavily exposed workers or accident victims in the 20 th century,there is a lack of evidence on chronic low to moderate PCDD/Fs exposure related respiratory damage,especially early respiratory effects.Lung function parameters,especially FVC(forced vital capacity)and FEV1(forced expiratory volume in 1s)can serve as early indicators of respiratory damage.Hence it is of significance to investigate the associations between individual PCDD/Fs exposure and lung function alternations.The mechanisms of PCDD/Fs caused pulmonary damage remain unclear.Previous toxicological studies have shown that PCDD/Fs can induce oxidatively generated damage and inflammation.Meanwhile,oxidative stress and inflammation have been confirmed to play central roles in the pathogenesis of some respiratory diseases like COPD,asthma and lung cancer.Nevertheless,whether and how oxidative stress and inflammation take part in PCDD/Fs induced respiratory effects is still unknown.Based on the aforementioned research background,this study was conducted on the workers of a foundry plant in Hubei,and the general residents living 5 km away from the plant were selected as the references.Demographic information,urine,and peripheral blood samples of each participant were collected,their lung function was measured.Meanwhile,the air and food samples were collected from the plant and residential community respectively.PCDD/Fs in the air,food and serum samples were determined.Urinary 8-oxod G and 8-iso PGF2α as biomarkers of oxidative damage,serum CRP,IL-1β,TNF-α,IL-6 and IL-17 concentrations as inflammation biomarkers were measured.Firstly,PCDD/Fs concentrations in the air,food samples were determined,to estimate the external PCDD/Fs exposure through air inhalation and food ingestion.Serum PCDD/Fs concentrations were used as the biomarker for internal PCDD/Fs exposure.The dominant exposure pathways and the associations between external and internal PCDD/Fs exposure for the workers and residents were analyzed.Secondly,the dose-response associations between external/ internal PCDD/Fs exposures and lung function levels were analyzed.Finally,based on above analyses,the mediation models were used to explore potential mediation effects of oxidative damage and inflammation biomarkers on the associations between PCDD/Fs exposures and lung function levels.Part 1.PCDD/Fs exposure estimation of the foundry workers and general residentsObjective: To investigate the PCDD/Fs levels of the air and foods in the daily environment of the foundry workers and residents,to estimate external/internal PCDD/Fs exposure and the main exposure sources of the participants.Methods: The workers from one foundry plant in Hubei were selected as the occupationally exposed group,and the residents living in a residential community locating 5 km away from the plant were selected as the references in this study.Every participant provided their urine and venous blood samples,questionnaire surveys and physical examinations were conducted on them.Meanwhile,ambient air samples were collected from inside/outside of the foundry workshop and the community,seven kinds of food samples were bought from the supermarkets or wet market near the plant and community.After cleanup procedures,HRGC/HRMS was applied to detect the seventeen 2,3,7,8 substituted PCDD/F congeners.Due to the limitation of the research budget(about 10,000 yuan per sample),71 foundry workers were randomly selected according to the job categories using the method of stratified random sampling.And 47 gender and age matched residents were selected,summing up to 118 participants whose serum PCDD/Fs were determined.Toxic equivalent(TEQ)concentration of each of the seventeen PCDD/Fs congener is the product of the mass concentration and the corresponding toxicity equivalence factor,adding up to the total TEQ concentration of the sample.Based on the questionnaire information,PCDD/Fs exposure via air inhalation during workhours and off-work hours were estimated by formulas.Exposures via food ingestion were calculated by PCDD/Fs concentrations of the food and intake parameters.The sum of inhalation exposure and ingestion exposure was considered as the total external PCDD/Fs exposure.The internal exposure levels were represented by PCDD/Fs concentrations in the serums.Correlation and regression analyses were conducted to analyses the association between external and internal PCDD/Fs exposures.Results: A total of 444 participants with completed data of questionnaire and physical examinations were included in this study,comprising of 213 foundry workers and 231 general residents.There was no significant difference between the distributions of gender,age,weight,tobacco smoking habits,educational level and annual family income among the workers and residents.Compared with the general residents,the foundry workers were taller.The distributions of passive smoking habbits and regular physical were significantly different among the foundry workers and the general residents.From high to low,mean PCDD/Fs concentrations of the ambient air samples from the three sampling areas were: 0.27 pg TEQ/m3 inside of the foundry workshop,0.08 pg TEQ/m3 outside of the workshop and 0.07 pg TEQ/m3 of the air samples from the residential community.PCDD/Fs concentrations of the air samples from the three main worksites in the foundry workshop were: 0.43 pg TEQ/m3 of the surface treatment area,0.26 pg TEQ/m3 of the shakeout area,0.11 pg TEQ/m3 of the casting area.PCDFs were the predominant congeners in the air of the foundry plant,especially high-chlorinated congeners,while PCDDs were the predominant congeners in the air of the residential community.PCDD/Fs concentrations in the food samples from the wet market near the plant,the supermarket near the plant and the supermarket in the residential community were at similar level,with the mean concentration of 0.012 pg TEQ/g wet weight.Mean PCDD/Fs concentration in the meat samples was 0.016 pg TEQ/g wet weight,much higher than that of the vegetable samples(0.003 pg TEQ/g wet weight).The median value of the estimated PCDD/Fs exposure levels of the foundry workers was 134.15 fg TEQ/(kg body weight*day),among which exposure through air inhalation account for 60.93%.The median value of the estimated PCDD/Fs exposure levels of the residents was 75.73 fg TEQ/(kg body weight*day),among which exposure through air inhalation account for 75.85%.Total exposure of the workers was about 1.77 times of the residents,inhalation exposure of the workers was about 4.36 times of the residents.As for the internal exposure levels,the median value of serum PCDD/Fs concentrations of the workers was 8.38 pg TEQ/g lipid,about two times of the residents(4.18 pg TEQ/g lipid).According to the results of correlation analyses,inhalation exposure,ingestion exposure and total exposure of PCDD/Fs and PCDFs were correlated with corresponding internal exposures(all P<0.05).The regression analyses revealed that each 1-unit increase in ln-transformed concentration of PCDD/Fs exposure(fg TEQ/(kg body weight*day))was associated with 0.25 pg TEQ/g lipid increase in ln-transformed serum PCDD/Fs,after adjusting for gender,age,body mass index,smoking status,drinking status and physical exercise as the confounders.Conclusions: The PCDD/Fs level inside of the foundry workshop was much higher than that of the areas outside of the workshop and the residential community.For the foundry workers,inhalation exposure was the primary PCDD/Fs exposure pathway,while for the general residents,food ingestion contributed mostly to the PCDD/Fs of the general residents.Both external and internal PCDD/Fs exposure of the workers were higher than the residents.External PCDD/Fs exposure of the subjects were positively correlated with internal PCDD/Fs exposure.Part 2.Associations of PCDD/Fs exposure and lung function levels among foundry workers and general residentsObjective: To investigate the relationships between external/internal PCDD/Fs exposure and lung function levels.Methods: Twenty-two participants who failed to complete height or lung function measurements were excluded from the total participants of this part of study.Finally,423 subjects including 201 workers and 222 residents were included in this part.We further measured the lung function parameters(FVC and FEV1)of all participants according to the American Thoracic Society recommendations.Z scores of FVC and FEV1 were calculated by the estimation model via the application program released by the European Respiratory Society.On the basis of the results from the first part of the study,generalized linear model was used to explore the associations between ln-transformed PCDD/Fs external/internal exposure and absolute value and Z-scores of FVC and FEV1,adjusting for confounders including gender,age,height,weight,smoking status,drinking status,passive-smoking status,physical exercise,educational level and annual family income.Subgroup analyses were conducted to observe the influences of the grouping variables.Results: Among all participants,the mean age was 42.56 years old,there were 298 males,accounting for 70.45%.There was no significant difference between the distributions of gender,age,height,weight,tobacco smoking and alcohol drinking habits and educational level among the workers and residents.The absolute values and Z scores of FVC and FEV1 of the foundry workers were significantly lower than the residents(all P<0.05).Among the workers,adjusting for age,gender,height,weight,smoking and drinking status,passive smoking status,physical exercise,educational level and family income,the least square means of FVC,FEV1,Z-FVC and Z-FEV1 of the workers with longer seniority(>22 years)were lower than those with shorter seniority(≤22 years),but the differences were not statistical significant(P>0.05).Results of the multivariate regression analyses revealed that the FVC and Z-FVC levels of the foundry workers showed decreasing trends along with increasing PCDD/Fs exposure levels(Ptrend<0.05),no trend of FEV1 and Z-FEV1 along with PCDD/Fs exposure was observed.Among the general residents,FVC and FEV1 levels showed decreasing trends along with increasing PCDD/Fs exposure levels(Ptrend<0.05),no trend of Z-FVC and Z-FEV1 along with PCDD/Fs exposure was observed(Ptrend>0.05).In all subjects,each 1-unit increase in ln-transformed concentration of PCDD/Fs exposure(fg TEQ/(kg body weight*day)was associated with 0.48 L,0.26 L,0.95 and 0.61 decrease in FVC,FEV1,Z-FVC and Z-FEV1,respectively.Each 1-unit increase in ln-transformed concentration of inhalation PCDD/Fs exposure(fg TEQ/(kg body weight*day)was associated with 0.30 L,0.14 L,0.62 and 0.34 decrease in FVC,FEV1,Z-FVC and ZFEV1,respectively(P<0.01).Each 1-unit increase in ln-transformed concentration of ingestion PCDD/Fs exposure(fg TEQ/(kg body weight*day)was associated with 0.39 L,0.34 L,0.63 and 0.76 decrease in FVC,FEV1,Z-FVC and Z-FEV1,respectively(P<0.01).The inverse associations between PCDD/Fs exposure and lung function parameters remained to be significant when the participants were stratified by smoking status(P trend<0.01).FVC levels declined with increasement of all congeners(Ptrend<0.05)except 1,2,3,7,8,9-Hx CDD,FEV1 levels declined with increasement of all congeners(Ptrend<0.05)except 1,2,3,4,7,8-Hx CDD and 1,2,3,4,7,8-Hx CDF.In the subgroup analyses,lung function levels of both smokers and non-smokers declined with increasing PCDD/Fs exposure.Among the subgroup of participants whose serum PCDD concentrations have been measured,the foundry workers were divided into three groups according to their serum PCDD/Fs concentrations.Compared with the residents,the FVC,FEV1,Z-FVC and ZFEV1 levels of the workers presented significantly decreasing trends along with increasing serum PCDD/Fs tertiles(Ptrend<0.01).Combining the workers and the residents,the lung function of all participants showed decreasing trends along with increasing serum PCDD/Fs concentrations(Ptrend<0.01).Each 1-unit increase in ln-transformed concentration of serum PCDD/Fs(pg TEQ/g lipid)was associated with 0.36 L,0.22 L,0.74 and 0.56 decrease in FVC,FEV1,Z-FVC and Z-FEV1(P<0.05),respectively.Each 1-unit increase in ln-transformed concentration of serum ∑PCDFs(pg TEQ/g lipid)was associated with 0.18 L,0.12 L,0.39 and 0.31 decrease in FVC,FEV1,Z-FVC and ZFEV1,respectively(P<0.05).Each 1-unit increase in ln-transformed concentration of serum PCDDs(pg TEQ/g lipid)was associated with 0.14 L decrease in FEV1(P<0.05).FVC levels declined with increasement of 1,2,3,7,8-Pe CDD(Ptrend<0.05);1,2,3,7,8-Pe CDF and 2,3,4,7,8-Pe CDF,FEV1 levels declined with increasement of 1,2,3,7,8-Pe CDD(Ptrend<0.05).Conclusions: Lung function levels of the foundry workers were lower than the general residents.Lung function levels of the subjects were inversely associated with external/internal PCDD/Fs exposures.Part 3.The mediation roles of oxidative damage and inflammation in the associations between PCDD/Fs exposure and lung functionObjective: To investigate the relationships of PCDD/Fs exposure and oxidative damage and inflammation biomarkers,and to further explore the mediation effects of oxidative damage and inflammation biomarkers in the associations between PCDD/Fs exposures and lung function decline.Methods: The research subjects of this part were the same as part 2.Urine samples of all participants were collected.Urinary 8-oxod G concentrations were detected by HPLCECD to reflect the DNA damage level,urinary 8-iso PGF2α were detected by ELISA to serve as the biomarkers of lipid peroxidation.CRP,IL-1β,TNF-α,IL-6 and IL-17,which are closely related with respiratory injury in previous studies,were selected as indicators of inflammation.Serum concentrations of above five cytokines were measured by ELISA.Generalized linear model was used to explore the associations between above five indicators and PCDD/Fs external/internal exposure and lung function levels,adjusting for potential confounders.Mediation analyses were constructed to further explore the mediation effects of oxidative damage and inflammation indicators in the associations between PCDD/Fs exposure and lung function levels.Results: Urinary concentrations of 8-oxod G and 8-iso-PGF2α of the foundry workers were significantly higher than those of the general residents(P<0.01).Results of generalized linear models showed that,urinary 8-oxod G and 8-iso-PGF2α presented an upward trend with increasing PCDD/Fs exposure(Ptrend<0.01).Each 1-unit increase in ln-transformed concentration of total PCDD/Fs exposure was associated with 0.65 nmol/mmol creatinine and 0.38 ng/mmol creatinine increase in urinary 8-oxod G and 8-iso-PGF2α,respectively.These associations remained significant after subgrouped by smoking status.Lung function presented a downward trend with increasing urinary 8-oxod G and 8-iso-PGF2α(Ptrend<0.01).Each 1-unit increase in ln-transformed urinary 8-oxod G was associated with 0.14 L,0.07 L,0.31 and 0.18 decrease in FVC,FEV1,Z-FVC and Z-FEV1(P<0.05),respectively.Each 1-unit increase in ln-transformed 8-iso-PGF2α concentration was associated with 0.17 decrease in Z-FEV1(P<0.05).No significant relationship was observed between urinary 8-iso-PGF2α and FVC,Z-FEV1 and Z-FVC(P>0.05).The mediation analyses revealed that urinary 8-oxod G played a mediation role in the associations of estimated PCDD/Fs exposure with FVC and Z-FVC,with a mediation proportion of 11.73% and 13.17%,respectively.In the associations between PCDD/Fs exposure and FEV1,mediation effect of urinary 8-oxod G had not been observed.Besides,we did not find the mediation effect of urinary 8-iso-PGF2α.Urinary 8-oxod G concentrations presented an upward trend with increasing PCDD/Fs exposure(Ptrend<0.01).Each 1-unit increase in ln-transformed concentration of serum PCDD/Fs was associated with 0.32 nmol/mmol creatinine and increase in urinary 8-oxod G.We did not find the associations between serum PCDD/Fs and urinary 8-isoPGF2α.Each 1-unit increase in ln-transformed urinary 8-oxod G was associated with 0.36 L,0.23 L,0.75 and 0.58 decrease in FVC,FEV1,Z-FVC and Z-FEV1,respectively.Each 1-unit increase in ln-transformed urinary 8-iso-PGF2α was associated with 0.28 L,0.17 L,0.58 and 0.44 decrease in FVC,FEV1,Z-FVC and Z-FEV1,respectively(all P<0.05).The mediation analyses revealed that urinary 8-oxod G played a mediation role in the associations between FVC,FEV1,Z-FVC,Z-FEV1 with serum PCDD/Fs concentrations,with a mediation proportion of 29.05%,28.81%,29.42% and 28.53%,respectively.Besides,we did not find the mediation effect of urinary 8-iso-PGF2α.TNF-α and IL-17 were below the detectable concentrations in more than half of the urine samples,so only CRP,IL-1β and IL-6 were included in the analyses of this part of study.There was no significant difference between serum level of CRP of the foundry workers and the general residents(P>0.05).Neither were the IL-6 concentrations(P>0.05).While serum concentrations of IL-1β of the foundry workers were significantly higher than those of the general residents(P<0.01).Results of generalized linear models showed that,serum IL-1β concentrations presented an upward trend with increasing PCDD/Fs exposure(Ptrend<0.01).Each 1-unit increase in ln-transformed concentration of total PCDD/Fs exposure was associated with 7.65 pg/ml increase in serum IL-1β(P<0.01).No significant correlation was observed between estimated PCDD/Fs exposure with CRP and IL-6.We did not find the mediation effect of serum IL-1β.Among the subgroup of participants whose serum PCDD concentrations have been measured,each 1-unit increase in ln-transformed serum PCDD/Fs concentration was associated with 4.82 pg/ml increase in IL-1β.No significant correlation was observed between estimated PCDD/Fs exposure with CRP and IL-6.Each 1-unit increase in ln-transformed serum IL-1β was associated with 0.01 L and 0.03 decrease in FVC and Z-FVC,respectively.The mediation analyses revealed that serum IL-1β played a mediation role in the associations between FVC with serum PCDD/Fs concentrations,with a mediation proportion of 14.21%.Conclusions: Urinary 8-oxod G,8-iso-PGF2α and serum IL-1β presented upward trend along with increasing external/internal PCDD/Fs exposure.Urinary 8-oxod G played partly mediation roles in the associations between external/internal PCDD/Fs exposure and lung function.Serum IL-1β played mediation roles in the associations between internal PCDD/Fs exposure and lung function.Oxidatively generated DNA damage and IL-1β related inflammation may be involved in PCDD/Fs induced respiratory injury.In this study,we determined the PCDD/Fs concentrations in peripheral blood of the foundry workers and the general residents,in the air and food samples from their daily environment,to provide more accurate estimation of individual PCDD/Fs exposure.We found that inhalation of PCDD/Fs from the foundry work was the main PCDD/Fs exposure pathway of the workers,while ingestion of PCDD/Fs in daily foods was the main PCDD/Fs exposure pathway of the general residents.External and internal PCDD/Fs exposure of the foundry workers were both significantly higher than the general residents.Besides,PCDD/Fs exposure of the participants were dose-responsely correlated with lung function decline,which is a novel finding.Lastly,urinary 8-oxod G levels,serving as the biomarker of DNA oxidative damage,serum IL-1β levels,reflection inflammation response,both partly mediated the associations between PCDD/Fs exposure and lung function decline,providing possible clues for the mechanisms of PCDD/Fs induced respiratory damage.