ASSIGNMENT 3 ARKL KBI:

Please answer the following questions and include the sources of your references.

1. What is the main purpose of dose-response analysis in the context of environmental

health risk assessment?
2. Explain the concept of a "threshold dose" and how this concept is used in dose-response
analysis.
3. In dose-response analysis, what is meant by NOAEL (No Observed Adverse Effect
Level)?
4. Compare NOAEL with LOAEL. In what situations is each used?
5. Which model is most commonly used to describe the dose-response relationship of
carcinogenic substances? Linear non-threshold model/Sigmoid model/Log-normal
model/Quadratic model? Explain why.
6. Why is the linear non-threshold model often used for carcinogenic substances?
7. What is meant by Reference Dose (RfD) and Reference Concentration (RfC)?
8. Explain the process of deriving the RfD value from toxicological data.
9. What is the role of animal studies in dose-response analysis, and how are their results
extrapolated to humans?
10. One approach to estimating cancer risk in humans is by calculating the slope factor (SF).
Explain the meaning and use of the cancer slope factor in carcinogenic risk assessment.
11. In a dose-response graph, what does a sigmoid-shaped curve indicate?
o No dose-response relationship
o Constant effect across doses
o Increasing effect with dose until saturation
o Decreasing effect with increasing dose
12. Explain how dose-response curves can be used to estimate population risk at specific
environmental exposure levels.
Name : Muzakki Gusron Efendi
Student ID : 2210942013
Lecturer : Dr. Tivany Edwin, M.Eng

Environmental Health Risk Analysis – KBI

1. What is the main purpose of dose-response analysis in the context of environmental health
risk assessment?
The main purpose of dose-response analysis is to determine the relationship between the
magnitude of exposure (dose) to a chemical or environmental agent and the severity or
frequency of associated adverse health effects (response). This analysis helps identify safe
exposure levels and establish regulatory standards to protect public health.
• It is a key step in quantitative risk assessment, allowing for the estimation of risk levels at
various exposure doses.
• It also helps determine thresholds for toxicity and supports decisions regarding permissible
exposure limits.
Reference:
U.S. EPA (2012). Guidelines for Risk Assessment. https://www.epa.gov/risk/guidelines-risk-
assessment

2. Explain the concept of a "threshold dose" and how this concept is used in dose-response
analysis.
A threshold dose is the lowest dose at which a particular adverse effect is observed, or the
highest dose at which no adverse effect is observed. Below this dose, the body is assumed to
cope with the exposure without significant harm.
• In dose-response analysis for non-carcinogenic substances, the threshold dose is crucial for
defining safe levels.
• Regulatory agencies use this concept to derive reference doses (RfD) or tolerable daily
intakes (TDI) by applying uncertainty factors to the threshold dose.
Reference:
World Health Organization (WHO, 2009). Principles and Methods for the Risk Assessment
of Chemicals in Food. Environmental Health Criteria 240.

3. In dose-response analysis, what is meant by NOAEL (No Observed Adverse Effect Level)?
NOAEL stands for No Observed Adverse Effect Level, and it is the highest dose in a study at
which no statistically or biologically significant adverse effects are observed compared to the
control group.
• NOAEL is often used to identify a starting point for deriving reference doses (RfDs) for non-
carcinogenic substances.
• It assumes the existence of a threshold and is specific to the conditions and endpoints
measured in the study.
 Reference:
National Research Council (NRC, 1983). Risk Assessment in the Federal Government:
Managing the Process. National Academies Press.

4. Compare NOAEL with LOAEL. In what situations is each used?

Parameter NOAEL LOAEL
Definition No Observed Adverse Effect Level Lowest Observed Adverse Effect Level
Lowest dose at which adverse effects are
Meaning Highest dose without adverse effects
observed
Use Preferred for deriving RfDs Used when NOAEL is not available
Implication Indicates a safe exposure level Indicates a level where harm begins
• NOAEL is preferable in risk assessments, but when a NOAEL cannot be identified, LOAEL is
used with additional uncertainty factors to compensate.
Reference:
U.S. EPA (2002). A Review of the Reference Dose and Reference Concentration Processes.

5. Which model is most commonly used to describe the dose-response relationship of

carcinogenic substances?
Linear Non-Threshold (LNT) model is most commonly used for carcinogenic substances.
• It assumes any exposure, no matter how small, carries some risk of causing cancer.
• The model is used for its conservativeness and protective approach in public health policy.
• It extrapolates from observed data in high-dose animal studies to estimate risks at low
environmental exposure levels.
Reference:
U.S. EPA (2005). Guidelines for Carcinogen Risk Assessment.
https://www.epa.gov/risk/guidelines-carcinogen-risk-assessment

6. Why is the linear non-threshold model often used for carcinogenic substances?
The LNT model is used for carcinogens because:
• Carcinogenesis is often believed to result from a single mutation or a series of events that
can be initiated by even a single molecule of a carcinogen.
• There is no evidence of a safe threshold dose below which there is zero risk.
• It offers a conservative estimate of risk, aligning with public health protection goals.
Reference:
International Agency for Research on Cancer (IARC, 2006). Preamble to the IARC
Monographs.
U.S. EPA (2005). Guidelines for Carcinogen Risk Assessment.

7. What is meant by Reference Dose (RfD) and Reference Concentration (RfC)?

• RfD (Reference Dose) is an estimate of the daily oral exposure to a substance that is likely
to be without risk of adverse effects over a lifetime.
• RfC (Reference Concentration) applies similarly to inhalation exposures.
 Both are used by regulatory agencies (like the EPA) to set safe exposure limits for non-
carcinogenic substances.
Reference:
U.S. EPA (2022). IRIS Glossary. https://www.epa.gov/iris

8. Explain the process of deriving the RfD value from toxicological data.
Steps in deriving RfD:
1. Identify the Critical Study – usually an animal study or human epidemiological study.
2. Determine the Point of Departure (POD) – typically the NOAEL or LOAEL or a benchmark
dose (BMD).
3. Apply Uncertainty Factors (UFs) – to account for variability between species (animals to
humans), human variability, data gaps, etc.
4. Calculate RfD using the formula:
𝑷𝑶𝑫
𝑹𝒇𝑫 𝑼𝑭
𝑻𝒐𝒕𝒂𝒍
- RfD (Reference Dose):
The safe estimated daily exposure to a substance for humans, including sensitive
populations, over a lifetime (expressed in mg/kg/day).
- POD (Point of Departure):
The dose from a toxicological study where adverse effects start to appear or stop
being observed, such as:
• NOAEL – No Observed Adverse Effect Level
• LOAEL – Lowest Observed Adverse Effect Level
• BMDL – Benchmark Dose Lower Confidence Limit
- UFtotal (Total Uncertainty Factor):
A composite safety factor to address uncertainties in the data. Typically, it's a product
of several factors:
Reference:
U.S. EPA (2002). A Review of the Reference Dose and Reference Concentration Processes.
WHO (2009). Environmental Health Criteria 240.

9. What is the role of animal studies in dose-response analysis, and how are their results
extrapolated to humans?
Role of animal studies:
• Provide data on toxic effects, dose-response relationships, and mechanisms of action.
• Often used when human data are not available.
Extrapolation to humans involves:
• Using uncertainty factors (typically 10-fold) to account for inter-species differences.
• Considering dose-scaling methods (e.g., body surface area or weight).
• Applying pharmacokinetic and pharmacodynamic models if available.
Reference:
NRC (2007). Toxicity Testing in the 21st Century.
U.S. EPA (2011). Exposure Factors Handbook.
10. Explain the meaning and use of the cancer slope factor (SF) in carcinogenic risk assessment.
The Cancer Slope Factor (SF) represents the estimated risk of cancer per unit dose of a
carcinogen over a lifetime.
• It is the slope of the dose-response curve in the low-dose region and reflects increased
cancer risk per mg/kg/day.
• Used in the formula:
Risk = CDI * SF
Risk: The probability of an individual developing cancer over a lifetime due to the exposure
(a unitless number, e.g., 1 in 100,000.
CDI (Chronic Daily Intake): The average daily exposure to a carcinogen over a lifetime,
expressed in mg/kg/day.
SF (Slope Factor): Indicates increased cancer risk per unit intake of a substance, expressed
in (mg/kg/day)⁻¹. Derived from dose-response modeling of animal or human data.
Reference:
U.S. EPA (2005). Guidelines for Carcinogen Risk Assessment.
U.S. EPA IRIS Database. https://iris.epa.gov/

11. In a dose-response graph, what does a sigmoid-shaped curve indicate?

Increasing effect with dose until saturation
• A sigmoid-shaped curve shows a gradual increase in response at low doses, a steeper
increase at intermediate doses, and then a plateau where further increases in dose do not
increase effect.
• This is typical of many pharmacological and toxicological responses.
Reference:
Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition.

12. Explain how dose-response curves can be used to estimate population risk at specific
environmental exposure levels.
Dose-response curves help estimate how many people in a population might experience
adverse effects from a given environmental exposure by:
• Mapping exposure levels on the x-axis and health outcomes on the y-axis.
• Using epidemiological or toxicological data, the curve is used to interpolate or extrapolate
risk at observed or projected exposure levels.
• The area under the curve for a specific exposure range can represent the proportion of
the population at risk.
This helps in risk characterization and policy decision-making (e.g., setting maximum
contaminant levels in water or air).
Reference:
U.S. EPA (2012). Guidelines for Exposure Assessment.
WHO (2009). Environmental Health Criteria 240.