Exposure Assessment And Risk Characterization Of DEHP On A Worldwide Scale Using Epidemiological Data

Di（2-ethylhexyl）phthalate（DEHP）has been widely used as a plasticizer worldwide for decades.It has been restricted by many authorities for its reproductive toxicity and neurotoxicity,especially in toys and childcare products.Human biomonitoring studies have reported the urinary levels of DEHP metabolites of different populations.However,the geographic difference and the time trend of DEHP exposure levels among different age groups remain unclear in a worldwide scale.Besides,the current reference doses（RfDs）of DEHP are derived from no observable adverse effect level（NOAEL）or lowest observed adverse effect level（LOAEL）of animal studies,without applications of epidemiological evidence.The traditional NOAEL/LOAEL method can hardly utilize epidemiological data to derive RfDs or reflect the dose-response information.Instead,the benchmark dose（BMD）method is based on the best-fitting dose–response curve,which avoids the influence of study design and can derive a RfD closer to the true threshold.To solve these problems,this study utilized biomonitoring data extracted from epidemiological studies to estimate the exposure levels of different populations.Meanwhile,this study described the time trend of DEHP exposure levels and explored whether restrictions on DEHP had any positive influence in target populations.Furthermore,based on epidemiological data,BMD method was applied to derive the RfDs of DEHP for the critical effects of reproductive toxicity and neurodevelopment toxicity,and hazard ratios（HQs）were calculated to describe related risk.Part 1:Geographic distribution and time trend of human exposure of DEHP based on global biomonitoring dataObjective:This study aimed to elucidate the geographic distribution of DEHP exposure levels among different age groups and pregnant women,thus to further recognize populations of high risk.Also,this study aimed to analyze the time trend and explore the influence of regulations on the exposure levels in children.Methods:A thoroughly review of articles was conducted to collect biomonitoring data.Based on urinary concentrations of DEHP metabolites（MEHHP and MEOHP）,the estimated daily intakes（EDIs）were calculated to represent the exposure levels.Study populations were divided into the pregnant women group and different age groups,namely infants（≤1 year old）,children（2-11 years old）,adolescents（12-19 years old）,and adults（≥20 years old）.Grouped EDIs（EDI_Gs）were calculated by weighting EDIs on the sample size to represent the exposure level of one particular region or time period.Results:（1）Overall,143,182 samples from 45 nations/regions of 6 continents were included in this analysis with the sampling time ranging from 1982 to 2017.The average exposure level was 3.24μg/kg bw/day for general population.Children group suffered the highest exposure level（5.64μg/kg bw/day）,while infants and pregnant women had low exposure levels（1.78 and 1.89μg/kg bw/day,respectively）.（2）European showed a higher exposure level of 3.77μg/kg bw/day in general than that in Asia or North America.The EDI_G varied considerably between countries,with Iranians to be the highest（EDI_G=31.28μg/kg bw/day）.Comparison within China or the USA showed within-country variations.（3）The worldwide DEHP exposure level of general population preformed a downtrend from 4.76μg/kg bw/day before 2000 to 2.43μg/kg bw/day in the 2015-2017period.Along with the regulations on DEHP in childcare products and food contract materials,the EDI_Gs of corresponding children showed a delayed decrease.Conclusions:Vast difference existed in DEHP exposure levels.The high exposure level and special metabolic features imply that children are more vulnerable to DEHP exposure.The decrease tendency from 1980s related to the efforts of concerning policies and restrictions.The exposure levels should be kept monitoring to support the policies of pollutants control.More efforts should be taken to further protect populations of high risk.Part 2:Derivation of DEHP reference doses and health risk characterization based on epidemiological dataObjective:Focusing on the reproductive toxicity and neurodevelopment toxicity of DEHP,BMD method was used to derive RfDs using epidemiological data.Hazard quotients（HQs）were used to characterize DEHP exposure risk in different populations.Methods:Firstly,the toxicity data of DEHP were integrated,and literature review was conducted for different toxicities and exposure periods.For those studies meeting the data requirements of BMD method,data were extracted after quality evaluation.BMDS software was used to calculate BMDL values with the benchmark response of 10%.RfDs of male reproductive toxicity of adulthood and prenatal exposure,neurodevelopment toxicity of prenatal and childhood exposure were derived,namely RfD_rep-m,RfD_rep-p,RfD_neuro-p,and RfD_neuro-c.The corresponding hazard quotients(HQ_rep-m,HQ_rep-p,HQ_neuro-p,and HQ_neuro-c)were calculated based on the average EDI_G of target population,and the corresponding HQ_95th for high exposure risk was also calculated based on the 95^thquantiles of exposure level.In addition,the RfD of USEPA,which was based on hepatotoxicity observed in animals,was used to calculate the HQ_hep as a reference.Results:（1）Nine epidemiological studies were recognized for BMD calculation,and the final RfD_rep-m,RfD_rep-p,RfD_neuro-p,and RfD_neuro-c of DEHP were 3.1,2.3,2.8,and 10.8μg/kg bw/day,respectively.（2）The HQ_hepof general populations worldwide was 0.16.Only Iranians had a HQ_hepover 1.The HQ_hep-95thof people living in Greece,France and Saudi Arabia were over 1.（3）Among male adults,the HQrep-m of average exposure level was 0.89.HQrep-ms of Taiwan,Australia,South Korea,Israel,Denmark,Kuwait and Germany were over 1.The HQ_rep-m-95thof Chinese male adults was 2.73.Concerning the prenatal DEHP exposure,the HQ_rep-p of world average level was 0.82,with the HQ_rep-p of France,Spain,Greece,Mexico,Germany and the USA exceeding 1.Of the 13 countries with the 95^th exposure level reported,only Denmark had a HQrep-p-95th under 1.（4）As for the prenatal exposure and neurodevelopment toxicity,the HQ_neuro-p of world average level was 0.68.The HQneuro-ps of France,Spain,Greece,Mexico,and Germany exceeded 1.As for the childhood DEHP exposure,the worldwide average HQ_neuro-cwas 0.52.children of Iran,Saudi Arabia,and South Korea had HQ_neuro-c over 1,and the HQ_neuro-c-95thof Chinese children was 2.17.Conclusions:The RfDs derived in this study were lower than that of USEPA.The results of health risk assessment showed an unignorable risk of reproductive and neurodevelopment toxicity of DEHP exposure.The exposure sources of high exposure population should be further elucidated and more attentions should be paid to populations of high risk,such as pregnant women.Strategies are required to reduce the exposure risk of DEHP comprehensively.