基于貝葉斯的苯并(α)芘PBPK模型優(yōu)化與健康風(fēng)險評估應(yīng)用

孟祥暉,王宏洋*,孫宇巍,張明慧,朱光燦3*,沈亞琴,柳慧芳

基于貝葉斯的苯并(α)芘PBPK模型優(yōu)化與健康風(fēng)險評估應(yīng)用

孟祥暉1,2,王宏洋2*,孫宇巍2,張明慧2,朱光燦1,3*,沈亞琴2,柳慧芳2

(1.東南大學(xué)能源與環(huán)境學(xué)院,江蘇 南京 210096；2.中國環(huán)境科學(xué)研究院,環(huán)境基準(zhǔn)與風(fēng)險評估國家重點實驗室,北京 100012；3.東南大學(xué),環(huán)境醫(yī)學(xué)工程教育部重點實驗室,江蘇 南京 210096)

應(yīng)用基于生理的藥代動力學(xué)(PBPK)模型預(yù)測苯并(α)芘(BaP)暴露的人體內(nèi)部劑量,基于貝葉斯的馬爾科夫鏈蒙特卡洛模擬(MCMC)方法對模型參數(shù)進行校準(zhǔn)和優(yōu)化,最后運用已優(yōu)化的模型對BaP內(nèi)暴露基準(zhǔn)值進行推導(dǎo).研究發(fā)現(xiàn),基于貝葉斯的MCMC方法對模型后驗參數(shù)校準(zhǔn)后,模型精度明顯提高,兩個數(shù)據(jù)集驗證結(jié)果顯示殘差平方和分別降低了72%和94%.PBPK模型以BaP和子代謝物3-羥基苯并(α)芘(3-OHBaP)的體內(nèi)動力學(xué)過程為結(jié)構(gòu)基礎(chǔ),模擬BaP體內(nèi)濃度分布大小為脂肪>腎臟>皮膚>緩慢灌注組織>快速灌注組織>靜脈血>肝臟;3-OHBaP體內(nèi)濃度分布大小為腎臟>快速灌注組織>脂肪>肺>靜脈血>緩慢灌注組織>肝臟>皮膚.敏感性分析顯示,快速灌注組織-血分配系數(shù)對模型輸出影響最大,靈敏度系數(shù)超過了200%;排泄系數(shù)影響最小,只有腎小球過濾率KBR的靈敏度系數(shù)超過了1%.以美國國家環(huán)境保護局推薦的參考濃度2.0×10-6mg/m3為外暴露安全基準(zhǔn)值,基于PBPK模型推導(dǎo)了職業(yè)暴露的BaP生物監(jiān)測當(dāng)量(BE),結(jié)果顯示BE值為0.405pmol/mol肌酐(尿液3-OHBaP平均濃度),為基于人體內(nèi)暴露劑量水平進行定量健康風(fēng)險評估奠定了基礎(chǔ).

苯并(α)芘；貝葉斯統(tǒng)計；馬爾科夫鏈蒙特卡洛方法(MCMC)；基于生理的藥代動力學(xué)(PBPK)模型；3-OHBaP；生物監(jiān)測當(dāng)量

多環(huán)芳烴(PAHs)是環(huán)境中一類重要的持久性有機污染物,分布于自然界的各個角落[1].苯并(α)芘(BaP)作為PAHs中毒性最明確、致癌性最強的污染物受到了廣泛關(guān)注.研究表明BaP存在于烘烤食物、土壤、河湖沉積物和街道空氣等環(huán)境中,具有污染分布廣、持續(xù)時間長和危害作用大等特點[2–5].作為一種五環(huán)化合物,BaP體內(nèi)代謝過程復(fù)雜,在多種酶作用下迅速轉(zhuǎn)化為多種代謝產(chǎn)物(羥基化物、醌類、環(huán)氧化物等)[6].其中3-羥基苯并(α)芘(3-OHBaP)是解毒反應(yīng)的最終產(chǎn)物,相比較于其他代謝產(chǎn)物具有化學(xué)性質(zhì)穩(wěn)定和易檢測分析等優(yōu)勢,所以尿液3- OHBaP被認(rèn)為是一種反映BaP暴露情況的良好生物標(biāo)志物[6–10].

依據(jù)現(xiàn)有報道,目前對BaP的健康風(fēng)險評估一般是基于可接受的安全劑量標(biāo)準(zhǔn)和外暴露濃度[11–13].隨著3-OHBaP這種生物標(biāo)志物的研究不斷深入,基于3-OHBaP內(nèi)部劑量水平進行BaP健康風(fēng)險評估或許是一種更為科學(xué)的方式.這種內(nèi)暴露健康評估方法能夠反映不同途徑接觸污染物的綜合情況,摒棄了傳統(tǒng)方法中將多個途徑的風(fēng)險簡單相加的方式[14].雖然已經(jīng)有多個研究監(jiān)測并分析了人群中尿液3-OHBaP含量,但依然存在著BaP內(nèi)暴露基準(zhǔn)值缺失等問題,導(dǎo)致難以定量評估BaP內(nèi)暴露健康風(fēng)險,所以BaP內(nèi)暴露基準(zhǔn)值對于風(fēng)險評估和風(fēng)險管理尤為重要.

基于生理的藥代動力學(xué)(PBPK)模型是預(yù)測化合物在生物體內(nèi)劑量水平的數(shù)學(xué)模型,研究表明PBPK模型應(yīng)用于內(nèi)暴露健康風(fēng)險評估具有一定的優(yōu)勢[15-16].在BaP的人體PBPK模型研究中,存在著人體代謝動力學(xué)數(shù)據(jù)缺失和BaP物化參數(shù)誤差較大等缺陷,最終導(dǎo)致模型可靠性低[17].貝葉斯統(tǒng)計是一種基于概率分布分析未知參數(shù)不確定性的統(tǒng)計學(xué)方法,該方法是在已有的先驗信息基礎(chǔ)上,利用觀測數(shù)據(jù)估計未知參數(shù)的后驗概率分布[18].在多參數(shù)的貝葉斯模型中,通常利用馬爾科夫鏈蒙特卡洛(MCMC)方法進行高維度的數(shù)值積分運算.已有研究運用基于貝葉斯的MCMC方法估計PBPK模型參數(shù)后驗概率分布,模型驗證結(jié)果表明該方法是一種可靠的模型校準(zhǔn)和不確定性分析方法[19-20].

本文使用基于貝葉斯的MCMC方法對BaP和3-OHBaP 的人體PBPK模型參數(shù)進行了校準(zhǔn),分析討論了優(yōu)化后模型的準(zhǔn)確性和BaP與3-OHBaP在人體內(nèi)的動力學(xué)過程;并在PBPK模型基礎(chǔ)上,推導(dǎo)了BaP職業(yè)暴露內(nèi)暴露基準(zhǔn)值,即人體生物監(jiān)測當(dāng)量,為基于內(nèi)暴露的BaP定量健康風(fēng)險評估提供了支撐.

1 材料與方法

1.1 PBPK模型結(jié)構(gòu)和參數(shù)

圖1 BaP和代謝產(chǎn)物3-OHBaP的PBPK模型結(jié)構(gòu)

PBPK模型以生理學(xué)、生物化學(xué)和解剖學(xué)為基礎(chǔ),基于質(zhì)量守恒定律模擬化合物在生物體內(nèi)的吸收、分布、代謝和排泄等生理過程,并預(yù)測生物體內(nèi)部組織劑量.在人體內(nèi)暴露劑量難以檢測的情況下,該模型已廣泛應(yīng)用于污染物的藥代動力學(xué)和健康風(fēng)險評估研究[15,21].BaP是一種復(fù)雜大分子化合物,進入人體內(nèi)迅速代謝轉(zhuǎn)化為其他產(chǎn)物,所以本文考慮了BaP生物標(biāo)志物3-OHBaP的子模型.如圖1, BaP與3-OHBaP的PBPK模型結(jié)構(gòu)由肺部(Lung)、脂肪(Adipose Tissue)、皮膚(Skin)、腎臟(Kidney)、快速灌注組織(Richly Perfused Tissue)、緩慢灌注組織(Slowly Perfused Tissue)、肝臟(Liver)、靜脈血(Venous Blood)和動脈血(Arterial Blood)等九個房室構(gòu)成.模型各個腔室由血液循環(huán)聯(lián)系,依據(jù)質(zhì)量平衡關(guān)系建立常微分方程組對各個房室的BaP和3- OHBaP濃度進行求解,最終獲得濃度-時間曲線.其中,模型參數(shù)的初始值是依據(jù)已發(fā)表文獻:生理參數(shù)是以體重為70kg的成年人為標(biāo)準(zhǔn),借鑒Brown等[22]的成年人房室體積和血流量推薦值;物化參數(shù)涉及BaP和3-OHBaP在不同房室的分配系數(shù)和血-氣分配系數(shù)等;代謝參數(shù)依據(jù)最新人體肝臟微粒體代謝動力學(xué)的體外實驗數(shù)據(jù)[23];排泄系數(shù)考慮了3- OHBaP的肝腸循環(huán),即排泄過程中腸道對3-OHBaP的重吸收,該過程對3-OHBaP經(jīng)膽汁和腸道的糞便排泄有一定影響[24].

1.2 貝葉斯統(tǒng)計與MCMC方法

表1 PBPK模型參數(shù)先驗值

注:a 括號中是Levenberg-Marquarelt算法和Barbeau等[26]的數(shù)據(jù)集對模型進行初步擬合的先驗值; b取均值.

1.3 敏感性分析

對模型的后驗參數(shù)進行敏感性分析,確定模型中對特定模型輸出較為敏感的參數(shù).歸一化靈敏度系數(shù)(NSC)使用下列公式計算[27]:

式中:是模型輸出值;Δ是參數(shù)變化1%時模型輸出的變化量;是目標(biāo)參數(shù);Δ代表參數(shù)1%的變化量.歸一靈敏度系數(shù)的相對影響大小分類標(biāo)準(zhǔn)為低影響:|NSC|<20%;中影響:20%￡|NSC|<50%;高影響: |NSC|>50%[19].

1.4 生物監(jiān)測當(dāng)量

傳統(tǒng)人體健康風(fēng)險評估一般是基于污染物外暴露濃度,最近研究表明生物監(jiān)測結(jié)果可以反映污染物多途徑吸收、實際生物學(xué)接觸和混合物暴露情況等[14].人體生物監(jiān)測是對生物樣本中的生物標(biāo)志物進行檢測,生物樣本包括血液、尿液或其他介質(zhì),最終結(jié)果可以表征人體污染物內(nèi)暴露情況.Pletz 等[28]提出基于可接受的外暴露基準(zhǔn)值(如每日可接受攝入量TDI、參考劑量RfD、參考濃度RfC等)估計人體內(nèi)暴露基準(zhǔn)值的方法,將該基準(zhǔn)值定義為生物監(jiān)測當(dāng)量(BE).PBPK模型可以實現(xiàn)從外暴露安全基準(zhǔn)值到BE的轉(zhuǎn)化,將外暴露基準(zhǔn)值作為模型輸入,基于PBPK模型估算污染物或代謝物的內(nèi)部劑量基準(zhǔn)值,即為目標(biāo)物質(zhì)的BE值.在BE推導(dǎo)過程需要解決3個科學(xué)問題:1.可靠的外暴露基準(zhǔn)值;2.合適的生物標(biāo)志物;3.可靠的PBPK 模型.由于檢測技術(shù)的限制,3-OHBaP的檢出限較高,所以BaP的人體生物監(jiān)測研究主要集中在職業(yè)暴露領(lǐng)域[8],但BE基準(zhǔn)值的缺失導(dǎo)致無法基于生物監(jiān)測結(jié)果對職業(yè)人群內(nèi)暴露健康風(fēng)險進行定量估算.

美國國家環(huán)境保護局關(guān)于BaP的外暴露安全基準(zhǔn)值具有可靠的數(shù)據(jù)資料[13],結(jié)合已有的其他物質(zhì)BE推導(dǎo)方法理論和3-OHBaP研究現(xiàn)狀[8,28-29],本文基于優(yōu)化后的PBPK模型推導(dǎo)BaP職業(yè)暴露BE值.對于致癌效應(yīng),一般認(rèn)為大于零的所有劑量都有可能產(chǎn)生致癌風(fēng)險,即零閾量[30].所以本文首先推導(dǎo)BaP非致癌效應(yīng)BE基準(zhǔn)值,以BaP非致癌效應(yīng)的參考濃度2.0×10-6mg/m3作為外暴露基準(zhǔn)濃度[13],將一周作為一個工作周期,工作日每天工作8h,基于PBPK模型估算尿液中3-OHBaP濃度[31].該方法遵循了Hays等[32]提出的推導(dǎo)原則,將一周內(nèi)尿液中的3-OHBaP平均濃度作為BaP職業(yè)暴露BE基準(zhǔn)值.

2 結(jié)果與討論

2.1 模型驗證與敏感性分析

綜上,該研究基于貝葉斯和MCMC方法對模型參數(shù)進行了校準(zhǔn),優(yōu)化后的模型精度明顯提高.該方法所得到的后驗參數(shù)概率分布95%置信區(qū)間比先驗分布區(qū)間更小,降低了參數(shù)的不確定性.

表2 MCMC模擬參數(shù)先驗概率分布和后驗概率分布的中位值(2.5%,97.5%)

續(xù)表2

2.1.2 模型敏感性分析 敏感性分析以BaP和3-OHBaP的靜脈血濃度作為模型輸出,依據(jù)公式(1)計算模型優(yōu)化后各參數(shù)的歸一化靈敏度系數(shù).根據(jù)計算結(jié)果,選取歸一化靈敏度系數(shù)大于1%的參數(shù)見圖3.其中組織-血分配系數(shù)對模型具有較高的影響,特別是BaP快速灌注組織-血分配系數(shù)AT和BaP緩慢灌注組織-血分配系數(shù)PST.圖3(a)和(b)顯示AT的靈敏度系數(shù)最高,均超過了200%;ST的靈敏度系數(shù)也分別達到了104%和87%.這說明各個房室的吸收和分配作用顯著影響了BaP和3-OHBaP在靜脈血中的濃度,而快速灌注組織和緩慢灌注組織的影響最大.

另外,敏感性分析結(jié)果顯示代謝參數(shù)的靈敏度系數(shù)大多數(shù)在20%～50%,對模型輸出具有一定影響,這與Deng等[24]的結(jié)果類似.相比較對BaP靜脈血濃度的影響,M和MAX代謝參數(shù)對3-OHBaP靜脈血濃度的影響更高,靈敏度系數(shù)達到了30%;由于BaP在肝臟代謝轉(zhuǎn)化為3-OHBaP,轉(zhuǎn)化分?jǐn)?shù)會顯著影響3-OHBaP靜脈血濃度,靈敏度系數(shù)高達100%.人體模型和大鼠模型的敏感性分析結(jié)果也有一定差異,研究表明大鼠PBPK模型的代謝參數(shù)對模型的影響最高[36],這與本研究的人體模型結(jié)果有所不同,推測是大鼠和人類的代謝動力學(xué)差異導(dǎo)致的.

相對于吸收和代謝過程,排泄參數(shù)對BaP和3-OHBaP的靜脈血濃度影響不顯著.在影響3-OHBaP靜脈血濃度的參數(shù)中,只有腎小球過濾率BR的靈敏度系數(shù)超過了1%,達到22%.綜上,敏感性分析結(jié)果顯示各個房室的分配系數(shù)影響比代謝參數(shù)更高,排泄參數(shù)影響很低,這與Ortiz等[17]報道的PBPK模型敏感性分析結(jié)果具有差異,原因是該文獻的敏感性分析是將尿液3-OHBaP作為模型輸出值.

2.2 BaP與3-OHBaP體內(nèi)動力學(xué)分析

2.2.1 BaP體內(nèi)動力學(xué)分析 圖4(a)顯示了24h連續(xù)暴露0.1mg/m3BaP之后,人體內(nèi)BaP濃度隨時間的變化情況.由于肺部作為BaP吸入暴露的第一房室,前24h內(nèi)呈現(xiàn)持續(xù)高濃度的狀態(tài),所以BaP在房室的濃度大小排序也未考慮肺部.停止暴露后,第25h肺部BaP濃度急劇下降至0.456pmol/L,這與污染物吸入暴露的血液循環(huán)有關(guān): BaP首先在肺部歷經(jīng)動、靜脈血的交換,然后通過血液循環(huán)達到其他房室進行吸收、分配和代謝等動力學(xué)過程.其他房室BaP濃度在第26h也開始下降,35h之后下降至極小值.

如圖4(a),BaP在房室中的濃度大小:脂肪>腎臟>皮膚>緩慢灌注組織>快速灌注組織>靜脈血>肝臟.比較模型后驗參數(shù)的中位值,BaP的脂肪-血分配系數(shù)最高(AT中值為17.73),這是脂肪中BaP濃度最高的主要原因.Péry等[37]的大鼠PBPK模型解釋了BaP在大鼠脂肪和血液中的分配及擴散過程,其他研究也表明BaP具有高親脂性,易在生物體脂肪中富集[38].雖然肝臟-血分配系數(shù)比緩慢灌注組織-血分配系數(shù)高2倍以上,但結(jié)果顯示肝臟的BaP濃度比緩慢灌注組織中低得多,這是由于BaP主要在肝臟進行代謝.Crowell等[39]對小鼠、大鼠和女性的肝臟微粒體對BaP的體外代謝過程進行了實驗,計算了MAX和M等代謝動力學(xué)參數(shù),表明肝臟是BaP主要的代謝器官,其他大鼠動力學(xué)研究也證明了這個結(jié)論[36].針對其他的代謝器官,雖然Payan等[40]的大鼠[14C]-BaP暴露實驗顯示BaP在皮膚存在微弱的代謝和轉(zhuǎn)化過程,但具體代謝轉(zhuǎn)化機制尚未闡明.

2.2.2 3-OHBaP體內(nèi)動力學(xué)分析 如圖4(b),3- OHBaP在體內(nèi)的濃度上升和下降過程都比BaP緩慢,停留時間較長,每個房室的3-OHBaP濃度均小于BaP濃度,這是由于BaP在體內(nèi)的代謝過程復(fù)雜,3-OHBaP僅僅是BaP氧化產(chǎn)生的代謝物之一[6],在人體內(nèi)還存在多種BaP代謝物.3-OHBaP在體內(nèi)動力學(xué)的緩慢現(xiàn)象與生物監(jiān)測中職業(yè)工人尿液3- OHBaP的延遲排泄結(jié)果相吻合[26].

3-OHBaP在各個房室中的濃度大小:腎臟>快速灌注組織>脂肪>肺>靜脈血>緩慢灌注組織>肝臟>皮膚(圖4b).本研究發(fā)現(xiàn),與BaP的體內(nèi)動力學(xué)不同, 3-OHBaP在腎臟的濃度最高.比較3-OHBaP尿液排泄和糞便排泄的后驗參數(shù)分布,腎小球過濾率中位值為1.54,比膽汁排泄率和糞便排泄率中位值高1～2個數(shù)量級,這說明3-OHBaP的排泄過程中經(jīng)尿液的排泄途徑占主要,可能直接導(dǎo)致了腎臟中3-OHBaP的濃度最高.另一方面,雖然肝臟對BaP具有高度代謝作用[36,39],但模型模擬結(jié)果顯示肝臟的3-OHBaP濃度處于較低的水平.本研究發(fā)現(xiàn)3-OHBaP肝臟組織-血分配系數(shù)的后驗分布為0.34(0.11,0.69),相比較于其他組織-血分配系數(shù)低1個數(shù)量級,這可能是導(dǎo)致3-OHBaP在肝臟中濃度較低的原因.

2.3 尿液排泄與生物監(jiān)測當(dāng)量

隨著檢測技術(shù)不斷提高,已有較多研究監(jiān)測職業(yè)人群尿液中3-OHBaP濃度來評價接觸BaP的情況,并使用尿液肌酐校正水平來進行表征.Lutier等[41]對6名冶金工人的尿液樣本中3-OHBaP濃度進行了監(jiān)測,研究表明尿液3-OHBaP濃度為0.05～ 0.33nmol/mol肌酐.相比較于冶金工人,常年接觸燒烤的人群尿液3-OHBaP濃度更高,達到了0.98～ 2.67nmol/mol肌酐[10].經(jīng)過對職業(yè)工人尿液中3- OHBaP與環(huán)境BaP濃度的關(guān)系進行定量分析,結(jié)果發(fā)現(xiàn)大體呈現(xiàn)線性相關(guān)性[34].綜上,雖然有較多研究對職業(yè)工人尿液中3-OHBaP的濃度進行了監(jiān)測,但僅僅是對劑量水平、排泄特征等進行定性分析,并未根據(jù)監(jiān)測結(jié)果對人群接觸BaP的內(nèi)暴露健康風(fēng)險進行定量估算.

圖5 尿液中3-OHBaP濃度-時間曲線

本研究將BaP非致癌效應(yīng)的參考濃度2.0× 10-6mg/m3作為安全基準(zhǔn)值,以職業(yè)工人連續(xù)5d吸入暴露8h作為暴露場景,基于PBPK模型模擬一周內(nèi)尿液中3-OHBaP的排泄?jié)舛?圖5).研究發(fā)現(xiàn),尿液3-OHBaP峰值出現(xiàn)在當(dāng)日停止暴露后的6～8h,具有一定的延遲排泄現(xiàn)象;在一周的暴露周期內(nèi),最后兩天3-OHBaP尿液排泄?jié)舛鹊姆逯底罡?Lutier等[41]的生物監(jiān)測研究也表明3-OHBaP的尿液排泄具有延遲現(xiàn)象,采樣應(yīng)在輪班后第2d早上進行.在大鼠的BaP代謝動力學(xué)研究中發(fā)現(xiàn)3-OHBaP在腎臟有所累積,或許可以解釋這種延遲排泄現(xiàn)象[42].依據(jù)Boogaard等[43]報道的甲苯BE值推導(dǎo)方法,將一周內(nèi)尿液3-OHBaP的平均濃度0.405pmol/mol肌酐作為BaP的職業(yè)暴露非致癌效應(yīng)BE值(圖5虛線).若職業(yè)人群生物監(jiān)測中3-OHBaP的尿液平均濃度高于該BE值時,則暴露人群可能存在BaP非致癌風(fēng)險,但基于人體內(nèi)部劑量的非致癌風(fēng)險定量估算方法還需要進一步探索.

3 結(jié)論

3.1 基于貝葉斯的MCMC方法對BaP和3-OHBaP人體PBPK模型中的多參數(shù)進行了同步優(yōu)化,兩個數(shù)據(jù)集驗證結(jié)果顯示殘差平方和降低了72%和94%,后驗參數(shù)分布的置信區(qū)間相比先驗參數(shù)分布有所減小.

3.2 對PBPK模型模擬的BaP和3-OHBaP靜脈血濃度影響最大的是BaP快速灌注組織-血分配系數(shù),超過了200%.其他組織-血分配系數(shù)的歸一化靈敏度系數(shù)也處于較高水平.大部分代謝參數(shù)的靈敏度系數(shù)為20%～50%,但3-OHBaP轉(zhuǎn)化分?jǐn)?shù)對3- OHBaP靜脈血濃度的影響較高,靈敏度系數(shù)高達100%.排泄系數(shù)對BaP和3-OHBaP靜脈血濃度輸出影響較低.

3.3 BaP在房室的濃度大小為:脂肪>腎臟>皮膚>緩慢灌注組織>快速灌注組織>靜脈血>肝臟,脂肪中BaP濃度比其他組織器官高一倍以上.3-OHBaP在房室的濃度大小為:腎臟>快速灌注組織>脂肪>肺>靜脈血>緩慢灌注組織>肝臟>皮膚,3-OHBaP在各個房室中濃度上升和下降過程都更緩慢,其在腎臟的濃度最高,在肝臟的濃度處于較低水平.

3.4 以BaP非致癌效應(yīng)的參考濃度作為外暴露安全基準(zhǔn)值,將一個周期內(nèi)尿液3-OHBaP平均濃度作為生物監(jiān)測終點,推導(dǎo)出BaP職業(yè)暴露BE值為0.405pmol/mol肌酐,在一個工作周期內(nèi)的3-OHBaP尿液平均濃度高于該值則可能存在非致癌風(fēng)險.

[1] Kim K H, Jahan S A, Kabir E, et al. A review of airborne polycyclic aromatic hydrocarbons (PAHs) and their human health effects [J]. Environment International, 2013,60:71–80.

[2] Dimitriou K, Kassomenos P. The influence of specific atmospheric circulation types on PM10-bound benzo(a)pyrene inhalation related lung cancer risk in Barcelona, Spain [J]. Environment International, 2018,112:107–114.

[3] 周 煜,沈 毅,王姝婷,等.杭州市居民谷物和燒烤油炸類食品多環(huán)芳烴暴露風(fēng)險評估[J]. 預(yù)防醫(yī)學(xué), 2019,31(3):260-264,270.

Zhou Y, Shen Y, Wang S T, et al. Risk assessment of polycyclic aromatic hydrocarbons exposed from cereal, fried and grilled food in Hangzhou [J]. Preventive Medicine, 2019,31(3):260-264,270.

[4] 孟祥帥,陳鴻漢,鄭從奇,等.焦化廠不同污染源作用下土壤PAHs污染特征[J]. 中國環(huán)境科學(xué), 2020,40(11):4857-4864.

Meng X S, Chen H H, Zhen C Q, et al. Pollution characteristics of PAHs in soil at an abandoned coking plant affected by different sources [J]. China Environmental Science, 2020,40(11):4857-4864.

[5] 康 杰,胡 健,朱兆洲,等.太湖及周邊河流表層沉積物中PAHs的分布、來源與風(fēng)險評價[J]. 中國環(huán)境科學(xué), 2017,37(3):1162-1170.

Kang J, Hu J, Zhu Z Z, et al. Distribution, source and risk assessment of PAHs in surface sediments from Taihu Lake and its surrounding rivers [J]. China Environmental Science, 2017,37(3):1162-1170.

[6] 劉曉晨.苯并[a]芘暴露生物標(biāo)志物的研究[J]. 大連:大連醫(yī)科大學(xué), 2013.

Liu X C. Study on exposure biomakers of benzo(a)pyrene [D]. Dalian: Dalian Medical University, 2013.

[7] Richter B S, Dettbarn G, Jessel S, et al. Ultra-high sensitive analysis of 3-hydroxybenzo[a]pyrene in human urine using GC-APLI-MS [J]. Journal of Chromatography B, 2019,1118–1119:187–193.

[8] Zaj?c J, Dziedzina S, Zaj?c A, et al. Relationship between variants of detoxification genes and 3-hydroxybenzo[a]pyrene concentration in urine of coke plant workers [J]. Polycyclic Aromatic Compounds, 2020,40(1):1–12.

[9] Fernández S F, Pardo O, Hernández C S, et al. Children’s exposure to polycyclic aromatic hydrocarbons in the Valencian Region (Spain): Urinary levels, predictors of exposure and risk assessment [J]. Environment International, 2021,153:106535.

[10] Oliveira M, Capelas S, Delerue-Matos C, et al. Grill workers exposure to polycyclic aromatic hydrocarbons: Levels and excretion profiles of the urinary biomarkers [J]. International Journal of Environmental Research and Public Health, 2020,18(1):230.

[11] EPA, 2019. Guidelines for human exposure assessment [J]. Risk Assessment Forum U.S. Environmental Protection Agency: 223.EPA/ 100/B-19/001.

[12] 侯 榮,阿依博塔·吐爾遜別克,秦 寧,等.室內(nèi)空氣中苯并[a]芘的健康限值研究[J]. 中國環(huán)境科學(xué), 2020,40(5):434–441.

Hou R, Ayibota T, Qin N, et al. Research on benzo[a]pyrene criteria in indoor air [J]. China Environmental Science, 2020,40(5):2287-2294.

[13] EPA, 2017. Toxicological review of benzo[a]pyrene [R]. Integrated Risk Information System National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency. Washington, DC:EPA/635/R-17/003Fa.

[14] Louro H, Hein?l? M, Bessems J, et al. Human biomonitoring in health risk assessment in Europe: Current practices and recommendations for the future [J]. International Journal of Hygiene and Environmental Health, 2019,222(5):727–737.

[15] 劉 遠,王中鈺,陳景文,等.基于PBPK模型評價三氯乙烯的職業(yè)暴露健康風(fēng)險[J]. 生態(tài)毒理學(xué)報, 2019,14(4):83-91.

Liu Y, Wang Z Y, Chen J W, et al. Health risk assessment of occupational exposure to trichloroethylene based on PBPK model [J]. Asian Journal of Ecotoxicology, 2019,14(4):83-91.

[16] Zhang Y, Han X, Niu Z. Health risk assessment of haloacetonitriles in drinking water based on internal dose [J]. Environmental Pollution, 2018,236:899–906.

[17] Ortiz H R, Ma?tre A, Barbeau D, et al. Use of physiologically-based pharmacokinetic modeling to simulate the profiles of 3- hydroxybenzo(a)pyrene in workers exposed to polycyclic aromatic hydrocarbons [J]. PLoS ONE, 2014,9(7):e102570.

[18] 茆詩松,湯銀才.貝葉斯統(tǒng)計[M]. 2版.北京:中國統(tǒng)計出版社, 2012:237-241.

Mao S S, Tang Y C. The Bayesian statistics [M]. 2nd edition. Beijing: China Statistics Press, 2012:237-241.

[19] Chou W C, Lin Z. Bayesian evaluation of a physiologically based pharmacokinetic (PBPK) model for perfluorooctane sulfonate (PFOS) to characterize the interspecies uncertainty between mice, rats, monkeys, and humans: Development and performance verification [J]. Environment International, 2019,129:408–422.

[20] Ratier A, Lopes C, Labadie P, et al. A Bayesian framework for estimating parameters of a generic toxicokinetic model for the bioaccumulation of organic chemicals by benthic invertebrates: Proof of concept with PCB153 and two freshwater species [J]. Ecotoxicology and Environmental Safety, 2019,180:33–42.

[21] 宋 韜.基于PBPK模型的多環(huán)芳烴暴露人群劑量與健康風(fēng)險研究[D]. 廣州:暨南大學(xué), 2018.

Song T. Populational Dose and health risk assessment on polycyclic aromatic hydrocarbons based on PBPK model [D]. Guangzhou: Jinan University, 2018.

[22] Brown R P, Delp M D, Lindstedt S L, et al. Physiological parameter values for physiologically based pharmacokinetic models [J]. Toxicology and Industrial Health, 1997,13(4):407–484.

[23] Smith J N, Mehinagic D, Nag S, et al. In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes [J]. Toxicology Letters, 2017,269:23–32.

[24] Deng L, Liu H, Deng Q. Physiologically-based pharmacokinetic modeling of benzo(a)pyrene and the metabolite in humans of different ages [J]. International Journal of Environmental Health Research, 2019,31(2):202–214.

[25] Gelman D, Koch C P, Kosloff R. Dissipative quantum dynamics with the surrogate Hamiltonian approach. A comparison between spin and harmonic baths [J]. The Journal of Chemical Physics, 2004,121(2): 661–671.

[26] Barbeau D, Lutier S, Bonneterre V, et al. Occupational exposure to polycyclic aromatic hydrocarbons: relations between atmospheric mixtures, urinary metabolites and sampling times [J]. International Archives of Occupational and Environmental Health, 2015,88(8): 1119–1129.

[27] Lin Z, Fisher J W, Ross M K, et al. A physiologically based pharmacokinetic model for atrazine and its main metabolites in the adult male C57BL/6mouse [J]. Toxicology and Applied Pharmacology, 2011,251(1):16–31.

[28] Pletz J, Blakeman S, Paini A, et al. Physiologically based kinetic (PBK) modelling and human biomonitoring data for mixture risk assessment [J]. Environment International, 2020,143:105978.

[29] Apel P, Rousselle C, Lange R, et al. Human biomonitoring initiative (HBM4EU) - Strategy to derive human biomonitoring guidance values (HBM-GVs) for health risk assessment [J]. International Journal of Hygiene and Environmental Health, 2020,230:113622.

[30] 劉 柳,張 嵐,李 琳,等.健康風(fēng)險評估研究進展[J]. 首都公共衛(wèi)生, 2013,(6):264–268.

LIU L, ZHANG L, LI L, et al. Research progress on health risk assessment [J]. Capital Journal of Public Health, 2013,(6):264–268.

[31] Angerer J, Aylward L L, Hays S M, et al. Human biomonitoring assessment values: Approaches and data requirements [J]. International Journal of Hygiene and Environmental Health, 2011,214 (5):348–360.

[32] Hays S M, Becker R A, Leung H W, et al. Biomonitoring equivalents: A screening approach for interpreting biomonitoring results from a public health risk perspective [J]. Regulatory Toxicology and Pharmacology, 2007,47(1):96–109.

[33] Lafontaine M. Polycyclic aromatic hydrocarbon exposure in an artificial shooting target factory: Assessment of 1-hydroxypyrene urinary excretion as a biological indicator of exposure [J]. The Annals of Occupational Hygiene, 2000,44(2):89–100.

[34] Gendre C, Lafontaine M, Delsaut P, et al. Exposure to polycyclic aromatic hydrocarbons and excretion of urinary 3-hydroxybenzo[a] pyrene: assessment of an appropriate sampling time [J]. Polycyclic Aromatic Compounds, 2004,24(4/5):433–439.

[35] Kondo K, Wakasone Y, Iijima K, et al. Inverse analysis to estimate site-specific parameters of a mathematical model for simulating pesticide dissipations in paddy test systems [J]. Pest Management Science, 2019,75(6):1594–1605.

[36] Heredia O R, Bouchard M. Understanding the linked kinetics of benzo(a)pyrene and 3-hydroxybenzo(a)pyrene biomarker of exposure using physiologically-based pharmacokinetic modelling in rats [J]. Journal of Pharmacokinetics and Pharmacodynamics, 2013,40(6):669– 682.

[37] Péry A R R, Brochot C, Desmots S, et al. Predicting in vivo gene expression in macrophages after exposure to benzo(a)pyrene based on in vitro assays and toxicokinetic/toxicodynamic models [J]. Toxicology Letters, 2011,201(1):8–14.

[38] 張昭勇,歐莉莉,羅嘉瑩,等.空氣中多環(huán)芳烴在人體中的代謝反應(yīng)及其對吸入性過敏性疾病的影響機制[J]. 環(huán)境衛(wèi)生學(xué)雜志, 2017, 1(v.7):75–80.

Zhang Z Y, Ou L L, Luo J Y, et al. Metabolic Response in Human Body to Air Polycyclic Aromatic Hydrocarbons and their Effects on Inhalant Allergic Diseases [J]. Journal of Environmental Hygiene, 2017,1(v.7):75–80.

[39] Crowell S R, Hanson-Drury S, Williams D E, et al. In vitro metabolism of benzo[a]pyrene and dibenzo[def,p]chrysene in rodent and human hepatic microsomes [J]. Toxicology Letters, 2014,228(1): 48–55.

[40] Payan J-P, Lafontaine M, Simon P, et al. 3-Hydroxybenzo(a)pyrene as a biomarker of dermal exposure to benzo(a)pyrene [J]. Archives of Toxicology, 2009,83(9):873–883.

[41] Lutier S, Ma?tre A, Bonneterre V, et al. Urinary elimination kinetics of 3-hydroxybenzo(a)pyrene and 1-hydroxypyrene of workers in a prebake aluminum electrode production plant: Evaluation of diuresis correction methods for routine biological monitoring [J]. Environmental Research, 2016,147:469–479.

[42] Marie C, Bouchard M, Heredia O R, et al. A toxicokinetic study to elucidate 3-hydroxybenzo(a)pyrene atypical urinary excretion profile following intravenous injection of benzo(a)pyrene in rats [J]. Journal of Applied Toxicology, 2010,30:402–410.

[43] Boogaard P J, Hays S M, Aylward L L. Human biomonitoring as a pragmatic tool to support health risk management of chemicals – Examples under the EU REACH programme [J]. Regulatory Toxicology and Pharmacology, 2011,59(1):125–132.

Optimization of benzo (α) pyrene PBPK model based on bayes and its application in health risk assessment.

MENG Xiang-hui1,2, WANG Hong-yang2*, SUN Yu-wei2, ZHANG Ming-hui2, ZHU Guang-can1,3*, SHEN Ya-qin2, LIU Hui-fang2

(1.Southeast University School of Energy and Environment, Nanjing 210096, China；2.State Key Laboratory of Environment Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China；3.Key Laboratory of Environmental Medical Engineering, Ministry of Education, Southeast University, Nanjing 210096, China)., 2022,42(5)：2370～2378

The physiologically based pharmacokinetic(PBPK) model was used to predict the human internal dose of benzo(α)pyrene(BaP) exposure. The parameters of the model were optimized based on bayes statistics and Markov Chain Monte Carlo simulation (MCMC), and the optimized model was adopted to derive the reference value regarding the internal dose of BaP. It was found that the accuracy of the model was significantly improved after calibrating the posterior parameters by Monte Carlo simulation, and thevalidation results of two datasets showed that the sums of squared residuals were reduced by 72% and 94%. The PBPK model was based on the pharmacokinetic of BaP and its metabolite 3-hydroxybenzo(α)pyrene(3-OHBaP). The internal concentration distribution of BaP followed the order of fat>kidney>skin>slowly perfused tissue>richly perfused tissue>venous blood>liver, while that of 3-OHBaP was in the order of kidney>richly perfused tissue>fat>lung >venous blood >slowly perfused tissue> liver>skin. Besides, the sensitivity analysis indicated that the rich perfused tissue-blood distribution coefficients showed the strongest influence on the model output, which sensitivity coefficient exceeded 200%. While the coefficients related to excretion showed the weakest influence, and only sensitivity coefficient of glomerular filtration rate KBRexceeded 1%. According to the reference concentration 2.0×10-6mg/m3recommended by U.S. Environmental Protection Agency, the biomonitoring equivalent of BaP was derived based on the optimized PBPK model. The results showed that the reference value for the occupational populations was 0.405pmol/mol creatinine (i.e., the mean concentration of 3-OHBaP in urine), which lays a foundation for the quantitative health risk assessment based on the human internal dose.

benzo(α)pyrene；bayes statistics；Markov Chain Monte Carlo(MCMC)；physiologically based pharmacokinetic (PBPK) model；3-OHBaP；biomonitoring equivalents

X592

A

1000-6923(2022)05-2370-09

孟祥暉(1997-),男,四川綿陽人,碩士研究生,研究方向為PBPK模型和環(huán)境人體健康.發(fā)表論文1篇.

2021-09-26

國家重點研發(fā)計劃項目(2021YFE0106600)

* 責(zé)任作者, 高級工程師, wanghongyang_why@126.com; 教授, gc-zhu @seu.edu.cn