CN109583662A - Atmosphere pollution binary mixture health risk assessment method - Google Patents
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Abstract
A kind of atmosphere pollution binary mixture health risk assessment new method, the following steps are included: obtaining pollutant concentration in atmosphere from document or actual environment monitoring, the pollutant for choosing approximate concentration is converted into external equivalent concentration as two end number mixing component to be evaluated, and by actual environment exposure concentrations；The transcript profile data of every kind of pollutant and the external biological test information of specific passageways are obtained from public database or document, calculate its melange effect numerical value, the correction relative efficiency factor and joint toxic action mode；Monte Carlo simulation is carried out to the external equivalent concentration of pollutant and couples the correction relative efficiency factor, evaluates the health risk of mixed pollutants.The present invention establishes on the basis of pollutant monomer environment exposure concentrations and biological test data, mixture toxicity data are not depended on, its health risk can be evaluated, save human and material resources cost, mixes the fields such as exposure health risk assessment and environmental safety assessment in actual environment and has broad application prospects.
Description
Technical field
The present invention relates to the health risk assessment technical fields of pollution mixing exposure, relate more specifically to a kind of atmosphere pollution
Binary mixture health risk assessment method.
Background technique
Problem of environmental pollution is always all not only the pollution problem of single chemicals.The dirt of broad categories in true environment
Dye object often exists in hybrid form, and is exposed to crowd and generates joint toxic effect.Since composite pollution synergy generates
Health effect complicated and changeable, Calculation Estimation joint toxicity and its health risk be all the time scientific circles concern difficult point and
Focus.Early in US National environmental sanitation Science Institute (National Institute of Environmental in 2013
Health Sciences, NIEHS) just point out should be to illustrate the health effect of environment mixture as its following priority research weight
One of point.Airborne fine particulate matter (Fine Particulate Matters, PM2.5) it is natural mixed system.With Atmospheric particulates
For (Particulate Matters, PM) pollution, gray haze is usually directed to sulfate, nitrogen oxides, polycyclic aromatic hydrocarbon
(Polycyclic Aromatic Hydrocarbons, PAHs), Polychlorinated biphenyls (Polychlorinated Biphenyls,
) and the pollution problem of the various chemical components such as toxic heavy metal PCBs.Even if main organic contamination component polycyclic aromatic hydrocarbon, in atmosphere
In be also by a variety of congeners mixing in a manner of occur, including well-known human carcinogen's benzo [a] pyrene (benzo
[a] pyrene, BaP).International cancer research institution (International Agency for Research on Cancer,
IARC) 2013 by outdoor air pollution and airborne fine particulate matter be classified as (the 1st group) carcinogenic to the mankind (http: //
www.iarc.fr/en/media-center/iarcnews/pdf/pr221_E.pdf).However, PM2.5Exposure in human class health
Influence not only because given area pollute composition it is different due between different regions there are significant difference, areal separate sources
Atmosphere pollution totally different health effect is also presented.Kan in 2005 et al. points out health shadow caused by Chinese air pollution
Sound is different from developed country.Laden et al. has found the PM of motor vehicle, coal-fired source2.5Often increase 10 μ g/m3, crowd is dead daily
Rate increases 3.4%, 1.1% respectively, and the fine particle health hazard in motor vehicle source is higher.As it can be seen that Accurate Prediction atmosphere pollution
The joint toxicity of mixture is its precondition for accumulating health risk of Scientific evaluation.
Regrettably, it can not show a candle to single pollutant poison about the progress of the non-experimental evaluation of mixture joint toxic action at present
The research of property prediction technique.Such as existing research application machine learning classification algorithm is to special to single chemicals in toxicity data library
Determine toxicity to be classified and predicted.No matter equivalent line chart or factor analysis method, during existing joint toxicity prediction model is established,
It is still indispensable for polluting the toxicity test data of mixture.Current atmospheric pollute health risk assessment mixture level still
Dependent on simple adduction it is assumed that concentrating on carcinogenic risk aspect of the Polycyclic Aromatic Hydrocarbon Mixture relative to BaP, and have ignored pollutant
Cause to underestimate risk there may be synergistic effect.Pollute mixture especially the mixture of mechanism complexity joint toxicity due to
Target spot and the mode of action are different and be more difficult analysis prediction in its organism.How to realize and is completely independent of mixture toxicity experiment
Joint toxicity Calculation Estimation be huge challenge and opportunity that pollutant toxicity prediction faces.
In conclusion the toxicity prediction method of single compound is gradually mature, and in environmental chemicals risk assessment
In be widely applied, and mixed chemical product generate complicated joint toxic effect be ecotoxicology research difficulties,
Its non-experimental evaluation method urgently develops.And it is limited by the limitation of joint toxicity research means, atmosphere pollution mixture health wind
Danger evaluation still is limited to the working hypothesis that pollution components toxicity is simply added, it is difficult to avoid risk and underestimate brought problem.Urgently
A kind of immediate toxicities prediction and evaluation method that component in conjunction binding mode close in the true mixed system of environment need to be developed, thus more
For the health risk and potential threat for objectively evaluating pollutant.
Summary of the invention
In view of this, the main purpose of the present invention is to provide a kind of atmosphere pollution binary mixture health risk assessment sides
Method, at least be partially solved at least one of above-mentioned technical problem.
As one aspect of the present invention, a kind of joint toxicity prediction technique of binary mixture, the binary are provided
Mixture includes two components that molar concentration is close, comprising the following steps:
Step 1: obtained from public database or document transcript profile data that two components expose respectively and with specific target spot
Or the testing in vitro data of the corresponding test terminal of access, it chooses the maximum component of two component Poisonings and is used as referring to body,
Another component referring to body, is obtained referring to body and the non-gene expression similarity mutual referring to body and referring to body and non-as non-
Monolithic dosage-effect curve equation of the test terminal of different target spots or access is corresponded respectively to referring to body；
Step 2: obtaining corresponding target spot respectively according to the monolithic dosage-effect curve equation or access is non-referring to body and ginseng
According to the testing in vitro medium effective concentration of body, and then obtain the non-relative efficiency factor referring to body relative to reference body；
Step 3: being calculated separately according to the gene expression similarity and monolithic dosage-effect curve equation referring to body or non-
To in the non-referring to body or referring to the gene residual effect of body generation of rear exposure when formerly being exposed referring to body, pass through described referring to body
The melange effect numerical value of binary mixture is obtained with non-gene residual effect, monomer effect referring to body, and then it is mixed to obtain binary
Object is closed relative to the correction relative efficiency factor referring to body；
Step 4: utilizing the non-reference body relative to the relative efficiency factor and binary mixture of reference body relative to ginseng
According to the power and effect of the joint toxic effect of the ratio characterization binary mixture changed between the correction relative efficiency factor of body
Mode.
As another aspect of the present invention, a kind of atmosphere pollution binary mixture health risk assessment method is provided,
The following steps are included:
Step A collects atmosphere pollution data by document or actual environment monitoring, obtains atmospheric samples in one period
In several pollutant concentration, choose two kinds of pollutants being close of molar concentration as binary mixture to be evaluated；
Step B, using joint toxicity prediction technique described in step 1~4, by the maximum pollution of binary mixture Poisoning
Object is used as referring to body, and another pollutant, referring to body, it is opposite relative to the correction referring to body to obtain binary mixture as non-respectively
Performance factors and the non-relative efficiency factor referring to body relative to reference body；
Step C, using the atmospheric concentration of non-reference body in the actual environment in the binary mixture as environmental exposure
The environmental exposure concentration conversion is external equivalent concentration by concentration；
Step D is opposite relative to the correction relative efficiency factor of reference body and non-reference body using the binary mixture
In the relative efficiency factor referring to body, in conjunction with the non-external equivalent concentration referring to body and referring to the toxicity action concentration of body, for
Corresponding target spot or access, carry out binary mixture health risk assessment.
Atmosphere pollution binary mixture health risk assessment method of the present invention has as follows known to based on the above-mentioned technical proposal
The utility model has the advantages that
(1) present invention fully considers pollutant gene in terms of mixture ambient health risk assessment joint toxicity assessment
The complicated toxic mechanism that express spectra variation is reacted is obtained by mapping that the testing in vitro data of specific passageways or target spot
It must cooperate with, the joint toxic action mode of the binary mixtures such as antagonism, compared to pollution components in existing Environmental Health risk assessment
The melange effect estimated value that the simple additive model of toxicity obtains is closer to truth；
(2) it present invention firstly provides the technical solution for the environmental pollution health risk assessment predicted based on joint toxicity, fills
Divide and combine existing transcript profile and biological test information, passes through gene residual effect method and estimate equal proportion binary mixture joint poison
Property, the coupling external equivalent concentration analogue data of pollutant carries out the health risk assessment of mixing exposure, application simulation sampling acquisition
The distribution of uncertain factor in the external equivalent concentration of pollutant, finally obtains scientific and reasonable health risk estimated value；
(3) joint toxicity evaluation method of the present invention directly establishes the transcript profile data and external work in pollutant monomer
In property test data, the toxicity test data for obtaining mixed system in advance are not needed, can predict binary mixture joint toxicity
And further it evaluates health risk, saves cost of human and material resources, method is quick, and high-efficient, this method is mixed in actual environment
The fields such as object health risk assessment, environmental safety assessment and mixture toxicity prediction are closed to have broad application prospects.
Detailed description of the invention
Fig. 1 is the embodiment of the present invention 1 using atmosphere pollution joint toxicity prediction progress health risk assessment schematic diagram；
Fig. 2 is that polycyclic aromatic hydrocarbon benzo [a] anthracene (BaA) and benzo [a] pyrene (BaP) docs-effect are bent in the embodiment of the present invention 1
Line schematic diagram；
Fig. 3 is that the health risk distribution density and cumulative probability of BaA monomer and binary mixture are shown in the embodiment of the present invention 1
It is intended to.
Specific embodiment
To make the objectives, technical solutions, and advantages of the present invention clearer, below in conjunction with specific embodiment, and reference
Attached drawing, the present invention is described in further detail.
According to the literature survey of the computation model to existing atmosphere pollution health risk assessment, it is seen that related method or
There are disadvantages for technology.Based on the toxicity prediction model simply summed it up, foundation in the hypothesis of independent action, is ignored between pollutant
Melange effect between pollutant.Often underestimate poisonous effect.It is a kind of based on combination transcription the invention aims to provide
The mixture of group data and specific passageways external biological test information combines toxicity prediction method, does not depend on the survey of priori mixture toxicity
Examination evaluates atmosphere pollution health by coupling atmosphere pollution exposure data.
General principles are, for specific target spot or access, two kinds of pollutant melange effects that exposure causes simultaneously
It is regarded as the gene residual effect that one of monomer exposure generates and the combined influence that another monomer exposure generates；Therefore
In combination with binary mixture in the test data in vitro of gene expression similarity and binary mixture monomer, two end number mixing is estimated
The melange effect of object.The joint toxicity mode of binary mixture and the strong and weak relative efficiency factor and binary for passing through pollutant monomer
The ratio characterization changed between the correction relative efficiency factor of mixture.Finally, passing through the correction relative efficiency of binary mixture
The factor and atmosphere pollution exposure data just obtain the distribution density and cumulative probability of atmosphere composite pollution health risk.
Document and patent search result show that present invention firstly provides the environmental pollution health wind predicted based on joint toxicity
The calculating solution nearly assessed.Before the present invention completes, do not find that also transcript profile data and biological test information will be based on,
And couple report of the external equivalent concentration analogue data of pollutant for the health risk assessment of atmosphere pollution mixture.
Firstly, the binary mixture includes to rub the present invention provides a kind of joint toxicity prediction technique of binary mixture
Two components that your concentration is close, such as two components of the molar concentration ratio between (1: 1.2)~(1.2: 1) comprising
Following steps:
Step 1: obtained from public database or document transcript profile data that two components expose respectively and with specific target spot
Or the monomer testing in vitro data of the corresponding test terminal of access, according to the literature or in two component of testing in vitro data decimation
The maximum component of toxicity is used as referring to body ref, and another component is as non-referring to body i, in which:
It is obtained using the transcript profile data referring to body ref and the non-gene expression similarity mutual referring to body i:
Wherein GiAnd GrefRespectively non-reference body i and the differential gene set referring to body ref, rI, refIndicate non-referring to body i
With the quantity referring to the common differential gene of body ref and referring to the ratio of body ref total difference gene dosage, rRef, iIndicate non-reference
Body i and quantity and the non-ratio referring to body i total difference gene dosage referring to the common differential gene of body ref, and 0≤rI, ref,
rRef, i≤1；
Using monomer external activity test data, target spot or the ratio of access response, are obtained as under different dosing dosage
Referring to body ref and the non-monolithic dosage-effect curve equation for corresponding respectively to different target spots or access referring to body i.
Step 2: obtained respectively according to the monolithic dosage-effect curve equation corresponding target spot or access k it is non-referring to body i and
Referring to the medium effective concentration of body ref, calculates its ratio and then obtain the non-relative efficiency referring to body i relative to reference body ref
The factor.
Specifically, this step includes:
It is obtained respectively by monolithic dosage-effect curve equation non-referring to body i and ginseng when causing target spot or access k response 50%
According to the monomer concentration of body ref, i.e. medium effective concentrationWithCalculate half referring to body ref and non-reference body i
The ratio of number effective concentration, the as non-relative efficiency factor referring to body i relative to reference body ref
Step 3: being calculated separately according to gene expression similarity and monolithic dosage-effect curve equation referring to body ref or non-
To in the non-referring to body i or referring to the gene residual effect of body generation of rear exposure when formerly exposing referring to body i, pass through the reference
Body ref and non-gene residual effect, monomer effect referring to body i obtain the melange effect numerical value of binary mixture, and then obtain
Binary mixture is relative to the correction relative efficiency factor referring to body ref.
Specifically, this step includes following sub-step:
Sub-step 31: non-reference is obtained respectively referring to body i and referring to monolithic dosage-effect curve equation of body ref by non-
Body i and the percentage f that causes target spot or access k respond is tested under exposure concentrations C in vitro referring to body refi C, k、
Wherein,It indicates k peak response percentage, is set as 100%；WithIt respectively indicates and draws
Send out non-reference body i and the non-monomer concentration referring to body ref when target spot or access k response 50%；N indicates that monolithic dosage-effect is bent
Line equation coefficient；
Sub-step 32: calculating under concentration C, if not it is special referring to body ref exposure initiation to equivalent when being exposed first referring to body i
The gene residual effect of targeting point or access kIt can be calculated from formula (4a):
Wherein rI, refFor the non-gene similarity referring to body i relative to reference body ref；It is doubling dose referring to body ref
Exposure causes the percentage of specific target spot or access k response；It indicates referring to body ref and non-reference body i biology
The effect of function same section；Indicate reference body ref biological function for non-reference body i
The effect of different piece；
Similarly, if non-to equivalent when exposing first referring to body ref cause specific target spot or the base of access k referring to body i exposure
Because of residual effectIt can be calculated from formula (4b):
Wherein rRef, iFor the gene similarity referring to body ref relative to non-reference body i；It is non-referring to body i for doubling dose
Exposure causes the percentage of specific target spot or access k response；Indicate non-referring to body i and referring to body ref biology function
The effect of energy same section；(1-rRef, i)fi C, kIndicate the biological function difference portion for referring to body ref non-reference body i
The effect divided；
Sub-step 33: calculating under concentration C, and the non-of equivalent successively exposes the specific target spot of initiation referring to body i and referring to body ref
Or the specific melange effect numerical value of access kThe non-monomer effect f referring to body i can be passed throughi C, kWith gene residual effectIt is calculated:
Similarly, under concentration C, the reference body ref of equivalent and non-successively expose referring to body i cause specific target spot or access k
Specific melange effect numerical valueIt is calculated by formula (5b):
Sub-step 34: comprehensively considering under concentration C, it is non-referring to body i and referring to body ref successively exposure cause specific target spot or
The melange effect numerical value of access kWith referring to body ref and non-referring to body i, successively exposure causes the mixed of specific target spot or access k
Close effect numerical valueIt is calculated non-referring to body i and the melange effect numerical value caused referring to the exposure of body ref simultaneous equal
Sub-step 35: it is calculated according to sub-step 31~34 at 0~20 timesIt is equally spaced multiple in concentration range
(such as 10000) concentration C, the non-of equivalent cause target spot or access k responds referring to body i and referring to body ref exposure simultaneously is lower
Melange effect numerical valueObtain the dose-effect relationship of binary mixture；
Sub-step 36: it is obtained according to sub-step 35When corresponding binary mixture in monomerAnd binary mixture is calculated relative to the correction relative efficiency factor referring to body refSuch as formula
(7) shown in:
Step 4: the power and binding mode of the joint toxic effect of binary mixture can be by such as formulas (8) with non-reference body
I relative to referring to body ref the relative efficiency factor and binary mixture relative to referring to body ref the correction relative efficiency factor it
Between change ratio characterization.I.e. in the presence of with/without referring to body ref, the exposure of binary mixture relative equality monomer causes specific
The change rate of target spot or access k toxicity:
If whereinAbsolute value is bigger, indicate in the case that referring to body ref exist, referring to body ref and it is non-reference body i
Common exposure generation joint toxic effect changes more significant compared to non-reference body i toxicity；If positive number, illustrate in reference
It is non-in the presence of body ref to enhance referring to body i toxicity, generate synergistic effect；If negative, illustrate referring to non-in the presence of body ref
Weaken referring to body i toxicity, generates antagonistic effect；If 0, illustrate referring to reference body i toxicity non-in the presence of body ref without change
Change, which is simple additive effect.
The present invention is based on aforementioned binary mixture joint toxicity prediction techniques, additionally provide a kind of atmosphere pollution two end number mixing
Object health risk assessment method, comprising the following steps:
Step A collects atmosphere pollution data by document or actual environment monitoring, obtains atmospheric samples in one period
In several pollutant concentration, choose one group of pollutant as mixed component to be evaluated, further, choose molar concentration rate
Two kind pollutants of the example between 1: 1.2~1.2: 1 are as binary mixture to be evaluated.
Step B, using joint toxicity prediction technique above-mentioned, using the maximum pollutant of binary mixture Poisoning as ginseng
According to body ref, another pollutant, referring to body i, obtains binary mixture relative to the opposite effect of correction referring to body ref as non-respectively
It can the factorAnd the non-relative efficiency factor referring to body i relative to reference body ref
Step C, using in binary mixture it is non-referring to body i in the actual environment atmospheric concentration as environmental exposure concentration,
It is external equivalent concentration by environmental exposure concentration conversion；
Specifically, every kind of non-external equivalent concentration EC referring to body i in two end number mixing component to be evaluatediAre as follows:
Wherein QCiFor the atmospheric concentration in the actual environment of a pollutant, i.e. environmental exposure concentration；AB is Chinese adult
People's respiratory rate；F is the ratio that pollutant contacts alveolar region, if QCiFor pollutant gas phase concentration, then f=1, if QCiFor pollutant
Particle phase concentration, then f is particulate matter alveolar deposition fraction；SA is alveolar region surface area；PSA is cell in testing in vitro experiment
The single hole surface area of culture plate；V is the one pore volume of tissue culture plate in testing in vitro experiment.
Step D, in conjunction with the non-external equivalent concentration EC referring to body ii, correction the relative efficiency factorRelatively
Performance factorsAnd the toxicity action concentration referring to body refFor specific target spot or access k, two are carried out
First mixture health risk assessment.
Specifically, this step includes following sub-step:
Sub-step D1: it is obtained by the monolithic dosage referring to body ref-effect curve equation and is causing target spot or access k response
PercentageWhen corresponding ref monomer concentrationI.e. referring to the toxicity action concentration of body ref；It can be obtained by referring to body ref monolithic dosage-effect curve equation inference, such as formula (10):
Sub-step D2, referring to body ref and the non-binary mixture referring to body i in corresponding target spot or the health risk of access k
Size activity ratioCharacterization indicates are as follows:
Wherein ECiFor the non-external equivalent concentration referring to body i；It is mixed for binary on corresponding target spot or access k
Object is closed relative to the correction relative efficiency factor referring to body ref；
Sub-step D3: non-reference body i is similarly obtained in corresponding target spot or the health risk of access k, with Pathway Activation ratioCharacterization indicates are as follows:
WhereinFor the non-external equivalent concentration referring to body i；It is non-referring to body i on corresponding target spot or access k
Relative to the relative efficiency factor referring to body ref.
Sub-step D4: for target spot or access k, by non-reference body i environmental exposure concentration QCiIt is exhaled with Chinese adult
Suction rate AB carries out Monte Carlo sampled analog, obtainsWithDistribution density and cumulative probability, characterize non-reference
The health risk of body i and the binary mixture referring to body ref composition.RA is strong in the bigger explanation of the 99th percentile of cumulative probability
Health risk is bigger.
It is further below by way of specific embodiment combination attached drawing in order to be more clearly understood that technology contents of the invention
Illustrate technical solution of the present invention.It should be noted that following embodiments are only for illustrating the present invention, rather than to the present invention
Limitation.
Embodiment 1
Polycyclic aromatic hydrocarbon is carcinogenic as known to it as a kind of typical toxic component being prevalent in Atmospheric particulates
Characteristic and adverse health influence, three kinds of polycyclic aromatic hydrocarbon congeners by U.S.'s noxious material and disease registration unit (ATSDR,
2015) it is classified as the top ten list of priority pollutant.The present embodiment is by integrating transcript profile data and testing in vitro data, with atmosphere
Illustrate atmosphere pollution binary mixture health risk assessment new method, process such as Fig. 1 for polycyclic aromatic hydrocarbon composite pollution in grain object
It is shown, specifically includes the following steps:
(1) Atmospheric Particulate Matter data collection.
From the concentration for obtaining polycyclic aromatic hydrocarbon in August, 2015 in March, 2016 Atmosphere of Beijing particle phase in document
(Sci.Total Environ., 2017,593-594,390-398).Two of them polycyclic aromatic hydrocarbon benzo [a] pyrene (BaP) and benzene
And the level of pollution of [a] anthracene (BaA) in non-heating season near 1: 1, table 1 lists 4 groups of concentration ratios in (1: 1.2)~(1.2
: 1) range typical case contamination data.BaP and BaA is chosen as binary mixture to be evaluated, wherein BaP is widely present in the environment
And it is more stable, it is the polycyclic aromatic hydrocarbon (IARC, 2010) for being uniquely classified as human carcinogen in IARC, it is considered to be in polycyclic aromatic hydrocarbon
The maximum monomer of toxicity.The effect that PAH other monomers form DNA adduct in human body cell is adjusted in existing document report BaP
Rate (Toxicology, 2014,321,27-39.).Therefore, reference body of the BaP as two end number mixing component is selected, BaA is as non-
Referring to body, the chemical structure of the two is shown below.
(2) binary mixture joint toxicity is predicted.
Firstly, after obtaining BaP and BaA difference direct oral cavity gastric infusion in document, 28 days male rat lung tissue samples
Microarray data originally (Arch.Toxicol., 2016,90,2461-2480；Toxicol.Sci., 2012,129,213-
224).Initial data the number of GEO database (https: //www.ncbi.nlm.nih.gov/geo/) be GSE43438 and
GSE51321.Gene expression chip data are read using the affy packet of R language and generate expression matrix, and RMA function is to gene number
According to being standardized, limma packet carries out differential gene extraction, retains the gene of correction p value (FDR)≤0.05 as significant
The gene of differential expression.The differential gene quantity of tri- compounds of BaP and BaA is respectively 1736 and 169.Secondly, according to it
The gene obviously adjusted is searched for from ToxCast toxicity data library (https: //actor.epa.gov/dashboard/) and is obtained
High-throughput body of the BaA and BaP on AhR (AEID:806), p53 (AEID:1321) and three kinds of accesses of NF- κ B (AEID:1346)
Outer test data.The AC of BaP and BaA50(μM) value and monolithic dosage-effect curve coefficient are as shown in table 2, monolithic dosage-effect
Curve is as shown in Figure 2.
Using the method for the invention, the high-throughput external biological test data and gene expression data of mixed component are obtained
Afterwards, the component BaP and BaA gene expression similarity r of binary mixture is calculated according to formula (1a) and (1b)BaA, BaPAnd rBap, BaA,
Respectively 0.005 and 0.050.
The BaA monomer phase on tri- kinds of access k of AhR, p53 and NF- κ B is calculated using BaP as referring to body according to formula (2)
For the relative efficiency factor of BaP monomer
According to formula (3)~(6), calculate separately at 0~20 timesIn concentration range equally spaced 10000 it is dense
It spends under the exposure of point C equivalent, the percentage that BaP monomer and BaA monomer respond on tri- kinds of access k of AhR, p53 and NF- κ BAnd melange effect specific value produced by binary mixtureThat is the dosage-of binary mixture
Effect relation.And it is back-calculated to obtainWhen binary mixture relative to BaP monomerThe results are shown in Table 3.
According to formula (7)~(8), the correction relative efficiency factor of the binary mixture relative to BaP monomer is calculatedAnd the relative efficiency factorWith the correction relative efficiency factorBetween
Relative change rateIt obtains on three kinds of accessesWithValue, respectively 0.346,0.15 and
0.14, and be all positive.In the case of illustrating that BaP exists, the toxicity of BaA enhances.Wherein, the prediction result on p53 access be based on
The binary mixture toxicity research result of experimental method it is consistent (Mutat Res.2007,620,123-134；
Toxicology.2011,279,36-44).
(3) binary mixture health risk assessment.
According to formula (9) by the environmental exposure concentration QC of pollutant in two end number mixing component to be evaluatedBaAIt is converted to external
Equivalent concentration ECBaA.Wherein QCBaAFor the concentration (nmol/m on pollutant BaA in the actual environment Atmospheric particulates3) (table 1)；
Since pollutant concentration data source is in Atmospheric particulates, f is the particulate matter alveolar deposition fraction (0.2350) of prediction, in advance
Measured value is from lung metering model software MPPD v3.04 (https: //www.ara.com/products/multiple-
path-particle-dosimetry-model-mppd-v-304)；SA is alveolar region surface area (75m2)；AB be China at
Year people's respiratory rate (14.5~18m3/day)；PSA is the single hole surface area that 1536 orifice plates are used in ToxCast testing in vitro
(0.023cm2)；V is the one pore volume (5 μ L) that 1536 orifice plates are used in ToxCast testing in vitro.
It is calculated separately on tri- kinds of accesses of AhR, p53 and NF- κ B according to formula (10),When corresponding BaP
Monomer concentrationAs the toxicity action concentration of risk object (referring to body), the results are shown in Table 3.
According to formula (11), external equivalent concentration ECBaAJoint respective channelsWith
Binary mixture Pathway Activation ratio is calculatedWithTo ECBaAIn not
Determine variable QCBaAThe distribution density and cumulative probability of RA (characterization health risk) are obtained by Monte Carlo sampled analog with AB,
Its 99th percentile of cumulative probability is respectively as follows: 0.23,0.10,0.041
Wherein Monte Carlo sampled analog obtains the environmental exposure concentration QC of 10000 BaABaAWith the sample of respiratory rate AB,
QCBaAIt is obtained according to the sampling that is uniformly distributed of BaA environmental exposure concentration, AB is obtained from the logarithm normal distribution of respiratory rate, for retouching
State the variation range of Chinese population respiratory rate.
Similarly according to formula (12), calculates and obtain BaA monomer Pathway Activation ratioWith
Distribution density and cumulative probability, the 99th percentile of cumulative probability is respectively as follows: 0.10,0.026,0.009.
The distribution density and cumulative probability result of the health risk of binary mixture and BaA monomer are as shown in Figure 3.By Fig. 3
Know that health risk of BaA with the BaP mixture on three kinds of accesses is compared BaA monomer and increased.From the figure 3, it may be seen that three kinds of accesses
Upper mixture is kept right compared to the RA distribution density of BaA monomer, illustrates the toxicity enhancing of BaA in the case of BaP exists, mixture may
Cause bigger health risk.It can be seen that the Pollution exposure data and biometric of pollutant monomer can be passed through by the method for the invention
The prediction of carry out mixture toxicity and the health risk assessment of data are tried, and does not depend on the biological test data of mixture.This method exists
Actual environment mixes the fields such as exposure health risk assessment and environmental safety assessment and has broad application prospects, and is expected to change
Product composite pollution health risk assessment provides technical support and guidance.
In conclusion the present invention will be polluted by making full use of existing external biological test data and transcription group information
Object joint toxic action model prediction is combined with actual environment exposure data, with the accumulation health risk of simulated environment mixture
Distribution.In particular, the method for the present invention is not about the precognition of the binding mode of chemical mixture it is assumed that melange effect is by mixing
The external dose-effect curve and transcript profile data-evaluation of single component determine in object.
Particular embodiments described above has carried out further in detail the purpose of the present invention, technical scheme and beneficial effects
Describe in detail bright, it should be understood that the above is only a specific embodiment of the present invention, is not intended to restrict the invention, it is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in protection of the invention
Within the scope of.
Subordinate list:
Concentration (the nmol/m of polycyclic aromatic hydrocarbon monomer in 1 atmospheric samples of table3)
The AC of polycyclic aromatic hydrocarbon monomer on 2 three kinds of accesses of table50(μM) value and dose-effect curve coefficient
The AC of polycyclic aromatic hydrocarbon binary mixture on 3 three kinds of accesses of table50The AC of (μM) and BaP10(μM)
Claims (10)
1. a kind of joint toxicity prediction technique of binary mixture, the binary mixture includes two groups that molar concentration is close
Point, which comprises the following steps:
Step 1: obtained from public database or document transcript profile data that two components expose respectively and with specific target spot or logical
The testing in vitro data of the corresponding test terminal in road are chosen the maximum component of two component Poisonings and are used as referring to body, another
Component, referring to body, is obtained referring to body and the non-reference mutual gene expression similarity of body and referring to body and non-reference as non-
Body corresponds respectively to monolithic dosage-effect curve equation of the test terminal of different target spots or access；
Step 2: obtaining corresponding target spot respectively according to the monolithic dosage-effect curve equation or access is non-referring to body and referring to body
Testing in vitro medium effective concentration, calculate its ratio so that obtain it is non-referring to body relative to referring to body the relative efficiency factor；
Step 3: being calculated separately according to the gene expression similarity and monolithic dosage-effect curve equation referring to body or non-reference
To the non-reference body in rear exposure or referring to the gene residual effect of body generation when body formerly exposes, by described referring to body and non-
The melange effect numerical value of binary mixture is obtained referring to gene residual effect, the monomer effect of body, and then obtains binary mixture
Relative to the correction relative efficiency factor referring to body；
Step 4: utilizing the non-reference body relative to the relative efficiency factor and binary mixture of reference body relative to referring to body
The correction relative efficiency factor between change ratio characterization binary mixture joint toxic effect power and binding mode.
2. joint toxicity prediction technique according to claim 1, which is characterized in that referring to body in the binary mixture
Ref and the non-molar concentration ratio referring to body i are (1: 1.2)~(1.2: 1).
3. joint toxicity prediction technique according to claim 1, which is characterized in that in step 1, it is described referring to body ref and
The non-gene expression similarity mutual referring to body i indicates are as follows:
Wherein GiAnd GrefRespectively non-reference body i and the differential gene set referring to body ref, rI, refIndicate non-referring to body i and ginseng
Quantity and the ratio referring to body ref total difference gene dosage, r according to the common differential gene of body refRef, iIndicate non-referring to body i
Quantity and the non-ratio referring to body i total difference gene dosage with the reference common differential gene of body ref, and 0≤rI, ref,
rRef, i≤1。
4. joint toxicity prediction technique according to claim 1, which is characterized in that step 2 specifically includes:
Obtain non-reference when the corresponding target spot of initiation or access k response 50% respectively according to the monolithic dosage-effect curve equation
Body i and monomer concentration referring to body ref, i.e. medium effective concentrationWithIt calculates referring to body ref and non-reference
The ratio of the medium effective concentration of body i, the as non-relative efficiency factor referring to body i relative to reference body refHave:
5. joint toxicity prediction technique according to claim 1, which is characterized in that step 3 specifically includes following sub-step:
Sub-step 31: it is obtained and non-is surveyed in vitro referring to body i and referring to body ref respectively by the monolithic dosage-effect curve equation
Try the percentage f for causing target spot or access k response under exposure concentrations Ci C, k、Have:
Wherein,It indicates k peak response percentage, is set as 100%；WithRespectively indicate initiation target
Non- reference body i and the non-monomer concentration referring to body ref when point or access k response 50%；N indicates monolithic dosage-effect curve side
Journey coefficient；
Sub-step 32: calculating under concentration C, if not particular target is caused referring to body ref exposure to equivalent when exposing first referring to body i
The gene residual effect of point or access kAnd if non-to equivalent referring to body i exposure initiation when being exposed first referring to body ref
The gene residual effect of specific target spot or access kHave:
Wherein, rI, refFor the non-gene similarity referring to body i relative to reference body ref, rRef, iIt is reference body ref relative to non-ginseng
According to the gene similarity of body i；Cause the percentage of specific target spot or access k response referring to body ref exposure for doubling dose；For the non-percentage for causing specific target spot or access k response referring to body i exposure of doubling dose；
Sub-step 33: calculating under concentration C, and non-successively expose referring to body i and referring to body ref of equivalent causes specific target spot or logical
The specific melange effect numerical value of road kAnd successively exposure causes specific target spot by the reference body ref and non-reference body i of equivalent
Or the melange effect numerical value of access kHave:
Sub-step 34: calculating under concentration C, and non-expose simultaneously referring to body i and referring to body ref of equivalent causes specific target spot or logical
The melange effect numerical value of road kHave:
Sub-step 35: it is calculated according to sub-step 31~34 at 0~20 timesUnder the equally spaced multiple concentration Cs of concentration range
The non-of equivalent causes the melange effect numerical value that target spot or access k are responded referring to body i and referring to body ref exposure simultaneouslyIt obtains
Obtain the dose-effect relationship of binary mixture；
Sub-step 36: it is calculated according to sub-step 35When corresponding binary mixture in monomerAnd calculate binary mixture relative to referring to body ref correction relative efficiency becauseHave:
6. joint toxicity prediction technique according to claim 1, which is characterized in that in step 4, the joint of binary mixture
Poisonous effect power and binding mode can by following formula with it is non-referring to body i relative to referring to body ref relative efficiency because
SonWith binary mixture relative to the correction relative efficiency factor referring to body refBetween the ratio that changes
Characterization:
If whereinAbsolute value it is bigger, indicate in the case that referring to body ref exist, referring to body ref and it is non-reference body i it is common
It is more significant referring to the variation of body i toxicity compared to non-that exposure generates joint toxic effect；If positive number, illustrate referring to body ref
In the presence of it is non-referring to body i toxicity enhance, generate synergistic effect；If negative, illustrate referring to non-reference in the presence of body ref
Body i toxicity weakens, and generates antagonistic effect；If 0, non-reference body i toxicity is unchanged in the presence of illustrating reference body ref, should
Binary mixture is simple additive effect.
7. a kind of atmosphere pollution binary mixture health risk assessment method, which comprises the following steps:
Step A collects atmosphere pollution data by document or actual environment monitoring, if obtaining in one period in atmospheric samples
Dry kind of pollutant concentration, two kinds of pollutants that selection molar concentration is close are as binary mixture to be evaluated；
Step B, using the joint toxicity prediction technique as described in claim 1 to 6 any one, by binary mixture Poisoning
Maximum pollutant is used as referring to body, and another pollutant, referring to body, obtains binary mixture relative to referring to body as non-respectively
The correction relative efficiency factor and it is non-referring to body relative to referring to body the relative efficiency factor；
Step C, using non-in the binary mixture referring to body atmospheric concentration in the actual environment as environmental exposure concentration,
It is external equivalent concentration by the environmental exposure concentration conversion；
Step D, using the binary mixture relative to the correction relative efficiency factor of reference body and non-reference body relative to ginseng
According to the relative efficiency factor of body, in conjunction with the non-external equivalent concentration referring to body and referring to the toxicity action concentration of body, for corresponding
Target spot or access, carry out binary mixture health risk assessment.
8. atmosphere pollution binary mixture health risk assessment method according to claim 7, which is characterized in that step A
In, choose molar concentration ratio be 1: 1.2~1.2: 1 between two kinds of pollutants as two end number mixing component to be evaluated.
9. atmosphere pollution binary mixture health risk assessment method according to claim 7, which is characterized in that step C
In,
The non-external equivalent concentration EC referring to body i in two end number mixing component to be evaluatediAre as follows:
Wherein QCiFor a pollutant atmospheric concentration, i.e. environmental exposure concentration in the actual environment；AB is Chinese adult respiratory rate；
F is the ratio that pollutant contacts alveolar region, if QCiFor pollutant gas phase concentration, then f=1, if QCiIt is mutually dense for contaminant particle
Degree, then f is particulate matter alveolar deposition fraction；SA is alveolar region surface area；SA is alveolar region surface area；PSA is external surveys
The single hole surface area of tissue culture plate in examination experiment；V is the one pore volume of tissue culture plate in testing in vitro experiment.
10. the method according to the description of claim 7 is characterized in that step D specifically includes following sub-step:
Sub-step D1 is obtained by the monolithic dosage referring to body ref-effect curve equation and is being caused the hundred of target spot or access k response
Divide ratioWhen corresponding ref monomer concentrationI.e. referring to the toxicity action concentration of body ref；
It can be obtained by referring to monolithic dosage-effect curve equation inference of body ref:
Sub-step D2, referring to body ref and the non-grade ratio binary mixture referring to body i in corresponding target spot or the health risk of access k
Use activity ratioCharacterization indicates are as follows:
Wherein ECiFor the non-external equivalent concentration referring to body i；For binary mixture on corresponding target spot or access k
Relative to the correction relative efficiency factor referring to body ref；
Sub-step D3: by it is non-referring to body i monomer corresponding target spot or access k health risk activity ratioCharacterization, table
It is shown as:
Wherein ECiFor the non-external equivalent concentration referring to body i；For on corresponding target spot or access k it is non-referring to body i relative to
Referring to the relative efficiency factor of body ref；
Sub-step D4: for target spot or access k, by the non-environmental exposure concentration QC referring to body iiIt is breathed with Chinese adult
Rate AB carries out Monte Carlo sampled analog, obtainsWithDistribution density and cumulative probability, RA is in cumulative probability
The 99th percentile bigger illustrate that health risk is bigger.
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