2010 3rd International Conference on Biomedical Engineering and Informatics (BMEI 2010)

Research on Risk Assessment Based on Monte Carlo

Simulation and Dose-response Multistage Model
Deyin Huang

Mao Liu, Jing Zhang, Yang Wang

Institute of Labor Hygeine

Tianjin Bohai Chemical Industry Group Co.
Tianjin 300051, China

Research Center of Urban Public Safety

Nankai University
Tianjin 300071, China

AbstractThe occupational hazard assessment of construction

project implemented currently in China plays an important role
in early prevention of occupational diseases. But the assessment
techniques and methods are mostly based on qualitative mode or
experience mode. There are still not unified and clear assessment
methods and quantitative models to evaluate the chronic and
potential cancer risk of chemicals. Because of the lack of scientific
quantitative assessment methods, the risk can not be assessed
quantitatively and scientifically. That also turns to be one of the
technical difficulties demanding prompt solution in occupational
hazards assessment. This paper introduced the risk assessment
technique based on Monte Carlo simulation and dose-response
multistage model. This method regarded the probabilistic risk of
cancer as assessment target, and mainly used in quantitative
assessment of cancer risk caused by chronic exposed to chemical
carcinogens. The widely adopted four-step assessment method
was used in health risk assessment, and it included hazard
identification, dose-response assessment, exposure assessment
and risk characterization. We used internal dose instead of
external dose in assessment, and it made the result more
accurate. The relationship between exposure dose and adverse
health effect is determined by multistage model. For the
uncertainty in exposure and risk assessment, we use Monte Carlo
simulation to analyze the probability distribution. This method
can be used practically in occupational hazards assessment and
provide a scientific basis to the control of occupational hazards
and the prevention and management of occupational tumor and
other serious occupational diseases.
Keywords- risk assessment, occupational cancer, Monte Carlo
simulation, dose-response model, workplace

I.

INTRODUCTION

The current situation of the occupational hazards in China

is very tense, the number of people that access to occupational
hazards is large, occupational hazards are widely distributed,
serious occupational hazards are not effectively controlled, the
economic losses and social impact caused by occupational
hazards are serious. The occupational hazards assessment of
construction project plays an important role in early prevention
of occupational diseases, and it has positive effect on
controlling the occurrence of occupational diseases effectively
in early period and relieving the grim situation of occupational
diseases prevention. Assessment of occupational hazards
mainly aims at occupational health risk in workplace, and the
assessment result is an effective technical basis for
occupational health risk management and the prevention and

controlling of occupational hazards in the workplace. However,

the current assessment technologies and methods are mostly
based on qualitative mode or experience mode, and the
research on quantitative assessment is seldom. Especially for
the chronic risk and potential cancer risk of chemicals, because
of the lack of unified and clear evaluation methods and
quantitative models, it is hard to implement scientific
quantitative assessment. That also turns to be one of the
technical difficulties demanding prompt solution in
occupational hazards assessment.
This study regarded the probabilistic risk of cancer as risk
target, used multistage dose-response model in assessment,
collected and analyzed epidemiological data and information
on animal experiments, assessed the uncertainty in assessment
quantitatively by using Monte Carlo simulation, and
implemented this method in occupational hazards evaluation
and risk management [1,2]. This paper mainly introduced the
basic framework, procedural steps and main techniques of the
risk assessment techniques based on Monte Carlo simulation
and dose-response multistage model. We also applied this
method in occupational hazard assessment of construction
project.
II. BASIC FRAMEWORK OF RISK ASSESSMENT BASED ON
MONTE CARLO SIMULATION AND DOSE-RESPONSE MULTISTAGE
MODEL

The widely adopted health risk assessment method is

published by American Academy of Sciences in 1983, it
contains four steps: hazard identification, dose-response
assessment, exposure assessment and risk characterization, risk
management, and we can call it four-step method[3]. According
to that method, we proposed the basic framework of risk
assessment based on Monte Carlo simulation and doseresponse multistage model. It described the procedures of
assessment and analysis; purpose of each step; information and
risk analysis method needed in each step. Besides the four step
mentioned above, we also proposed step 5: risk management.
The content of the basic framework is shown in TABLE .

Tianjin Natural Science Funds10JCYBJC13400

978-1-4244-6498-2/10/$26.00 2010 IEEE

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TABLE I.
Step
Hazard
Identification

Inherent hazards
of
physicochemical
property
Toxicological
effects
Data of animal
experiments,
etc.
Epidemiological
investigation
Route and dose
of exposure

Environmental
monitoring
data
of
workplace;
Biological
monitoring data and other
external
exposure
evaluation.
Determine the functional
relations
between
exposure
dose
and
internal dose with PBPK
model.

Calculate the probability

of cancer by using doseresponse
multistage
model.
Analyze the uncertain
factor by using Monte
Carlo simulation. Assess
the acceptable level of
risk by using ALARP
criteria [4] .
Sort management of risk
level and occupational
hazards of construction
project. The decision of
cancer risk management
and
emergency
management must be
made from the aspects of
engineering
measures,
occupational
health
management,
routine
practice, emergency plan,
health care policy and
occupational
health
training.

Dose-response
model
Monte Carlo
simulation
PBPK model
prediction

Monte Carlo
simulation

Risk characterization, risk

Risk
Management

Clarify the intensity and

frequency of carcinogenic
effect due to different
levels of exposure by
analyzing epidemiological
data
and
animal
quantitative research data.
Determine the relationship
between exposure and
frequency
of
specific
health effects, get the doseresponse relationship.
Assess the harmful factor
qualitatively
and
quantitatively
through
inquiring
survey,
environmental monitoring,
biological monitoring and
other methods. Estimate
the exposure level of the
occupational
exposed
population, and provide
reliable exposure data to
exposure-response
relationship
assessment
and risk assessment.
Determine the probabilistic
risk of cancer of the
exposed population by
integrating analyzing and
determining the results of
the first three stages, get
the risk of getting tumors
by exposing to certain
carcinogenic factor. Point
out the uncertain factors in
analysis procedure.
Analyze
the
nature,
reliability, uncertain factor
of the data and the
assumptions
made
in
derivation and estimation.
Determine whether the risk
can be accepted, analyze
decision of risk control,
and decide what action to
take to control risk,
implement
risk
management.

According to four-step method, health risk assessment

include: hazard identification, dose-response assessment,
exposure assessment and risk characterization. The four-step
method is shown in Fig.1.

Exposure assessment

Risk
Characterization

Identify the activities or

exposure that may cause
potential harmful effects to
health and the possible
reason
that
can
be
observed. Identify and
determine
potential
hazards.
Analyze
the
nature, type, mode, time
and space conditions,
actual possibility and
serious degree of the
hazards.

Information and
technology
Epidemiologic
data;
Toxicology
data;
Historical summary like
statistical data of cases of
occupational
diseases;
Incidence of occupational
cancer;
Occupational
history;
Operational
procedures;
Training
records; Existing laws,
regulations and standard
specification.
Analogism, check list and
experience are usually
used in this section.
Physiologically
based
pharmacokinetic (PBPK)
model
is
used
to
determine the relationship
between internal dose and
cancer risk. Monte Carlo
simulation is used to
analyze the uncertainty in
this section.

MAIN PROGRAMS AND THE KEY STEPS

Dose-response assessment

Exposure
Assessment

Purpose and content

III.

Hazard identification

Dose-response
Assessment

BASIC FRAMEWORK

PBPK model
prediction
On-site
environmental
monitoring

Figure 1. Procedures of risk assessment based on Monte Carlo simulation

and dose-response multistage model

In the process of cancer risk assessment, there are two key

steps: firstly, simulate and predict the internal dose of exposed
population under a certain exposure level in the workplace (e.g.
concentration of exposure makers in blood). Secondly, put the
data of internal dose into dose-response model, and get the
value of cancer risk. For the uncertainty in the process of
exposure assessment and cancer risk assessment, Monte Carlo
simulation is used to solve this problem. Fig.2 shows the key
steps in detail.
Exposure level in the workplace
(external dose)
PBPK model+ Mote Carlo simulation
Internal dose
Dose-response model+ Mote Carlo simulation
Cancer risk

Figure 2. The key steps of risk assessment

IV.

MAIN TECHNICAL CONTENT

According to the four-step method that widely used

internationally, we assess the cancer risk of chemical
carcinogen under occupational chronic exposure. It includes

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identifying the health hazards in the workplace, collecting

relevant data like toxicological response, animal
carcinogenicity experiments, epidemiological data, building
dose-response model, assessing internal exposure by PBPK
model according the actual exposure concentration in the
workplace. After that, we can get the cancer risk of long-term
exposed population.
The risk assessment based on Monte Carlo simulation and
dose-response multistage model regards probabilistic risk of
cancer as risk target and do quantitative research: Apply
PBPK model in exposure assessment, predict internal dose
from external dose. Apply multistage model in doseresponse assessment. Combine PBPK model and multistage
model, obtain the dose-response model aimed at exposure of
carcinogen, and determine quantitative relationship between
the concentration of chemicals in the workplace and the
probabilistic risk of cancer. For the uncertainties in exposure
assessment and risk assessment, apply Monte Carlo simulation
to research the probability distribution.
A. Hazard Identification
In this step, the data needed in hazard identification,
exposure assessment and dose-response assessment is
collected. It includes physical and chemical properties of
chemicals, route of exposure, toxicokinetics properties,
toxicological effects, long-term animal carcinogenicity
experimental data, epidemiological data of occupational
exposed population, and other related information.
Occupational history and site investigation: Inquiries and
site investigations are the most popular methods in collecting
data of exposure assessment. These methods can provide a
basis to analyze the characteristics of exposed population.
Besides that, the information of health effects gathered in
inquiries is an important basis of exposure assessment, and
sometimes it is even the only feasible way. The investigation
includes occupational history, the number, sex and age of
exposed people, route of exposure, duration of exposure,
protection conditions, etc.
Toxicological effects: It means the processes of absorption,
distribution and metabolism, mechanism of toxicity, the major
clinical symptoms and other related information. Combined
with the site investigation, we can choose the right type of
PBPK model.
B. Dose-response Model BuildingDetermination of
Multistage Model
Dose-response assessment is a process to quantitatively
assess the relationship between the exposure level of harmful
factors and the incidence of adverse health effect in exposed
population. That is the quantitative basis of risk assessment.
In this procedure, the relationship between internal dose
and the probability of cancer is determined through toxicology
theory, population epidemiological data, animal experimental
data, etc. The dose-response model of chemical carcinogens is
determined through multistage model. The goal is to estimate
the probability (Pr) of the occurrence of cancer during the

individuals lifetime if he exposed to an agent at dose D (the

monitoring concentration in the workplace) during lifetime.
Set d to be the average internal dose that got by PBPK
model, the cancer risk of the exposed population is:
Pr(d ) = P0 + (1 P0 ) F ( d )
Where, F(d) is the dose-response function, it expresses the
relationship between the internal dose of harmful chemicals
and the occurrence of tumor, it is a single-increasing function
that the value is between 0 and 1, F(0)=0. P0 is the probability
of cancer without occupational exposure.

Common classes of dose-response models were Probit

model, Logit model, Weibull model, One hit model, Multihit
model and Multistage model[5, 6].
Probit model

F (d ) = (a + b ln d )

Logit model

F (d ) = [1 + exp((a + b ln d ))]1

Weibull model

F (d ) = (1 exp(bd k ))

Multihit model

F (d ) = F [b nt n1 / (n)] exp(bt ) dt

One hit model

F ( d ) = [1 exp(bd )]

Multistage model

F (d ) = [1 exp( ai d i )]

i=0

At present, the most widely used mathematical model in

dose-response assessment is multistage model[7]. Multistage
model assumes that the occurrence of irreversible toxic effect
like carcinogenicity is the result of many different random
biological process (or event, stage). That means a target cell
must go through many stage of change before the irreversible
toxic effect (e.g. cancer) occur, and these changes are
irreversible and independent.
U.S. Environmental Protection Agency (EPA) also
recommend in the cancer risk assessment guideline that in
general condition, the multistage model should be used in
research of dose-response relationship[3]. That because the
multistage model agrees with the carcinogenic process that
accepted widely now that a normal cell should pass a series of
irreversible changes or stages before it turns into a malignant
cell. So in this paper, we choose multistage model and use
internal dose in cancer risk assessment.
In this method, the cancer risk of individual is not directly
related with exposure dose, but calculated by internal dose, that
means the value of dose in F(d) is the internal dose. After
determining the function relationship between exposure dose
and internal dose, we can get the internal dose and then put it
into the internal dose-response model to get the cancer risk.
This method can model the relationship between exposure dose
and health effect more accurately, and reduce the uncertainty in
risk assessment, so the result is closer to reality.
According to the statement above, the dose-response model
can be determined.

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Set d to be the average internal dose (e.g. the maximal

concentration of the metabolin in blood, Cmax) when the
exposure dose is D. The cancer risk is:
(1)
Pr(tumor | d ) = P0 + (1 P0 ) F (d )
Where F(d) is the multistage model that mentioned above.
If d can be expressed as a function of D, denoted by d=f(D).
f(D) can be obtained by pharmacokinetic analysis or relevant
epidemiological data fitting. Then the cancer risk at exposure
dose D is:
Pr(tumor | D) = P0 + (1 P0 ) F [ f ( D)]

Where P0 is the background tumor risk at dose 0.

C. Determination of Exposure Dose

As discussed above, the internal dose is used in the
multistage model. Internal dose can be obtained from
biological monitoring data of occupational groups or predicted
by mathematical model. As shown in Fig. 3.
Environmental
monitoring

Exposure
concentration

Biological
monitoring

Mathematical
simulation

Frequency
Absorption
coefficient

Exposure
dose

PBPK
model

Internal dose

Exposure characterization

Figure 3. Representation of exposure assessment

At present, the PBPK model is mainly used in drug

development, medication, toxicologic study, etc., but rarely
involved in occupational health risk assessment.

PBPK model assumes the body being comprised of

physiologically similar compartments. Each compartment
represented an organ or tissue group, and linked to the central
blood compartment by arterial and venous blood flow. The
exogenous chemicals absorbed by the body go into the
compartment with arterial blood and leave with venous blood.
In a certain compartment, the chemical can also go into or
leave without arterial or venous blood, like metabolized in liver
or excreted from kidney. The transport and transformation of
chemicals in compartments follow mass conservation principle.
The material balance equation of the compartment is
determined by physiological parameter, biochemical
parameters and dynamical parameter, and that is the
mathematical description of the model.
The organs and tissues in the body can be divided into two
types: one is richly-perfused tissues, like liver and kidney; the
other is slowly-perfused tissues, like skin and fat. Liver is
usually regarded as a separate compartment because it has
specific metabolic functions. Fat is also regarded as a separate
compartment when consider about fat soluble substance,
because fat has a greater partition coefficient towards fat
soluble substance. So we can get a PBPK model with five
compartments: blood, liver, richly-perfused compartment,
slowly-perfused compartment and fat. Blood compartment can
be replaced by blood-lung compartment when consider about
volatile substances. Currently, for most chemicals we can use
the five-compartment model. But when we consider about
benzene in practical case, we regard marrow as a separate
compartment, so it turns into a six-compartment model[2].
In industrial production, the mainly route of exposure is the
steam-form chemicals inhaled through respiratory tract. So we
mainly consider inhalation instead of ingestion and dermal
contact. The PBPK model involved in this study is consisted of
five tissue compartments: alveolar gas-exchange region (lung),
fat, slowly-perfused tissues (muscle and skin), richly-perfused
tissues (all organs except liver) and liver. We suppose the
metabolism only occurs in liver, and the metabolic rate can be
expressed with Michaelis-Menten equation. The fivecompartment PBPK model is shown in Fig. 4.

Qc
Cv
Cvf
Venous Blood

Physiologically based pharmacokinetic (PBPK) model

a) The choice of physiological atrioventricular
PBPK model is based on physiological properties,
biochemical
properties,
anatomical
properties
and
thermodynamic properties of toxicology. In toxicologic study,
toxicokinetics can be interchanged with pharmacokinetics, so
PBPK model can also be called PBTK (physiologically based
toxicokinetic) model.

Cin

Cvr
Cvs
Cvl

1)

Qp

Cex

Alveolar Space
Lung Blood

Fat

Richly Perfused Tissues

Slowly Perfused tissues

Liver

Qc
Ca
Qf
Ca
Qr
Ca
Qs
Ca

Arterial Blood

This study used the PBPK model to simulate the

distribution, metabolize and transformation process after the
occupational hazardous substances been inhaled, and get the
concentration of chemicals in tissues and organs. The PBPK
model is used here to determine the function relationship
between the external exposure dose in the workplace and the
internal dose. The internal dose can be obtained by integrating
the monitoring value in the workplace with the mathematical
model. This method introduces PBPK model into occupational
health risk assessment, and provide a basis for occupational
exposure assessment[8].

Ql
Ca

Vmax ,Km
Metabolism

Figure 4. Schematic representation of the five-compartment PBPK model

b) Determination of model parameters[9, 10]

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 PHYSIOLOGICAL PARAMETERS
The physiological parameters needed in PBPK model is
body weight, organ weight, pulmonary ventilation volume,
cardiac output and blood flow rate in tissue. These parameters
can be obtained from physiological anatomy information of
main experimental animals (rat, mouse, dog) and human. So in
practice, we can use these summing up and peer-reviewed data
directly except body weight or on some special cases.
In PBPK model, the weight of all the compartment is 91%
of total body weight, the remaining 9% is the weight of nail,
hair, bone and other tissues that have no effect on
pharmacokinetics process and do not need to considered in the
model. The blood flow volume of all compartments is equal to
cardiac output.
PARTITION COEFFICIENT OF TISSUES AND ORGANS
The partition coefficient is one of the main factors that have
relationship with the process that the volatile substances go into
the blood by breathing and distribute to tissues and organs. It
includes blood and air partition coefficient and tissue and blood
partition coefficient.
METABOLIC PARAMETERS
Metabolic process is involved in most PBPK model as one
of important clearance way. If we do not need to track a
specific metabolite or can not track because of information
insufficiency, we can express the metabolic process generally
with Saturable equation or Michaelis-Menten equation.
Maximum metabolic rate(Vmax) and Michaelis-Menten
constant(Km) are needed in this process.
ABSORPTION PARAMETER
Some substances go into the liver directly after absorbed by
gastrointestinal tract. In PBPK model we demonstrate this
process by transporting a certain quality of substances to liver.
2) Solution of the model
The differential form of mass conservation equations can
express the absorption, distribution and clearance of the
chemicals inhaled. According to mass conservation principle,
the quantity changed in each compartment in unit time=the
quantity goes into this compartment- the quantity leaves this
compartment + the quantity increased by metabolism the
quantity decreased by metabolism. For exogenous chemicals
the quantity increased by metabolism is usually not needed to
be considered. The differential equation of the rate of change of
the chemical concentration in each compartment can be
determined with the blood flow rate, the tissue/blood partition
coefficient and the tissue volume of the compartment.
At present, the differential form of mass conservation
equations are usually solved with related simulation software,
like ACSL, Berkeley MadonnaMatlab, etc. We can also use
numerical solution of Euler and Excel spreadsheet to solve the
equation without simulation software[2, 11].

Risk Characterization Calculation of Cancer Risk

Risk characterization is the last step of quantitative risk
assessment, and is the comprehensive analysis of the main
results got from the last three steps. According to the results of
hazard identification, exposure assessment and dose-response
assessment, the risk of harmful factor can be quantitatively
estimated and expressed. Then we should interpret the results
of assessment and discuss the process of assessment, especially
to the reliability and the uncertainty in first three steps. At last
the results can be provided to risk manager in the form of
formal documents, and it can be a basis when they make a
decision.
D.

The multistage model is used in cancer risk calculation:

Pr(tumor | d ) = P0 + (1 P0 ) F (d )
Where F(d) is the multistage model that mentioned above.

If d can be expressed as a function of D, denoted by d=f(D).

f(D) can be obtained by pharmacokinetic analysis or relevant
epidemiological data fitting. Then the cancer risk at exposure
dose D is:
Pr(tumor | D) = P0 + (1 P0 ) F [ f ( D)]

Where P0 is the background tumor risk at dose 0.

Then put the data of exposure level into the dose-response
model and calculate the cancer risk of exposed population.
E.

Monte Carlo Simulation

Uncertainty goes throughout the whole process of the
health risk assessment. In risk assessment, because of the
insufficiency of the information or inadequate understanding of
objective things we can not estimate the value and frequency of
some certain variable correctly, that is uncertainty. It is mainly
because the lack of adequate knowledge and measured data
about the physical and biochemical processes. So we must
analyze the uncertainty of the results in exposure and risk
characterization, and we also need to reduce the uncertainty by
using some technical treatments. After these treatments we can
provide more accurate information to risk manager or decision
maker, and it is helpful to risk management.
The source, type and nature of uncertainty are complicated,
but we can reduce the uncertainty by quantitative or qualitative
analysis. Monte Carlo simulation is one of the most popular
methods in parameter uncertainty study[12, 13] .

Monte Carlo simulation can describe the things and system

processes with random nature more realistically, the restriction
is less, the convergence velocity is unrelated to the dimension
of the problem, it can handle many cases in the same time, the
error is easy to determined, the program is simple and easy to
realize. The shortage is the convergence velocity is slow.
In practice, we recommend to use Crystal Ball software in
Monte Carlo simulation. Crystal Ball (CB) is developed by
Decisioneering, Inc. It is an easy-to-use and powerful Monte
Carlo simulation add-in to Microsoft Excel that allows analysis
of the risks and uncertainties. CB is widely used in financial,
scientific and engineering fields. It has a friendly interface and
can calculate the result for each scenario, generating a range of

1249

results, which is evaluated to assess risk. In addition to

statistics description, tendency chart and distribution of
relevant variables, CB also has function like sensitivity
analysis, correlation, and historical data fitting. The correlation
feature allows the user to link uncertain variable to account for
their positive or negative dependencies.
Crystal Ball software interface includes three status bar:
definition, operation and analysis. We define variable in
variable defined area, input data in data edited area, and then
run Monte Carlo simulation, after that we can also do some
mapping and statistical analysis operations.

level, minimize the adverse effects of harmful factors, and

provide scientific basis for prevention and control strategies.
The risk assessment technique based on dose-response
multistage model and Monte Carlo simulation introduced in
this paper regards the cancer probabilistic risk of chemicals as
risk characteristic, identifies the hazards of chemical
carcinogen in the workplace, collect the data about toxicology
reaction, animal cancer experiments, population epidemiology,
etc., determine the dose-response model, get the cancer risk of
long-term exposed population, and assess the cancer risk of
chemical carcinogen under occupational chronic exposure. This
method is very practical and should be improve in theory and
application. Using quantitative method to predict the cancer
risk of exposed population can provide a scientific basis to the
control of occupational hazards and the prevention and
management of occupational tumor and other serious
occupational diseases.
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Figure 5. Variable definition window

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[6]
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Figure 6. Data definition window
[8]

V. APPLICATION OF RISK ASSESSMENT TECHNIQUE BASED

ON DOSE-RESPONSE MULTISTAGE MODEL AND MONTE CARLO
SIMULATION
The health hazard caused by occupational exposed to
chemical carcinogen has caused widespread concern in the
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[9]

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