1

TOXICOLOGY
NEWSLETTER
“All endeavors in life involve finite risk. Risk Assessment is a tool to rate the
degree of risk and prioritize Risk.”

October, 2018

Basics of Chemical Risk Assessment

K.S. Rao1 and Shriharsh Bijargi2
1.Eurofins Advinus and 2.Freyr Software Services Private Limited

A. Preamble
In the past, I have requested and encouraged any one of you to write an
article on toxicological aspects that are useful to our readers and submit it to
Mr. Alex Thomas (Editor), as I have no intention of writing all articles.
However, this time on Risk Assessment, I have solicited comments by my
good friend Dr. Shriharsh Bijargi who is a practicing Risk Assessor.
Shriharsh, significantly improved the writing and contributed substantial and
critical aspects to this newsletter. Hence, it is a joint article between the two
of us.

B. Introduction
Risk assessment is a process for proactively identifying and quantifying risks
in all settings. Addressing the risk is a part of risk mitigation. Risk
assessment is a scientific process of evaluating the adverse effects caused by
a substance, activity, lifestyle, or natural phenomenon.
In this newsletter, risk assessment refers to the process of estimating the type
and magnitude of risk to human health posed by exposure to chemical
substances.
Effective risk assessment and mitigation plan is based on a series of steps
which involves
Editor 1. Identifying risks
Alex Thomas 2. Assessing the extent of the risk
+91-974-545-0045
alexthomas.a@gmail.com 3. Determining whether action needs to be taken to reduce the risk,
and then acting
4. Evaluating the results of the action taken

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Health-based risk assessment for humans can be performed by using 2

approaches. First and obvious approach is to look into the exposure data from
earlier human exposures. Such human evidence can be collated from clinical
trial data, individual cases reported during the post-marketing surveillance or
reported as clinical cases of toxicity. The advantage of this kind of data is its
direct usability in risk assessment without the need for any further
extrapolation. However, such collated human evidence may lack in the
toxicological details related to longer duration of exposure(chronic toxicity,
carcinogenicity) or exposure during the different vulnerable state (pregnancy,
lactation, neonatal age, etc.) which can be provided from well-conducted
animal studies. Hence, the judgment of use of available human exposure data
and animal study data with extrapolations is one important judgment safety
assessor should make.
Assessments of human health risks combine information on the substance
exposure and the potential of a substance to cause toxicity. Within the
evaluation of exposure data and the potential of a substance to cause toxicity,
there can be data gaps. These data gaps are filled-in using some assumptions.
Such assumptions are generally made considering the worst-case approach.
While reporting the risk assessment assumptions should be clearly defines
along with the detailed discussion on harm and its magnitude.
The uncertainty is inherent in risk assessment, means that risk assessors
cannot precisely describe the risk. Rather, they should state the range of
probabilities which they found. Whilst recognizing that risk can never be
eliminated, effective channeling of resources for identifying and reducing risk
is sound business and healthcare practice which offers protection to humans.
When it comes to chemical management, a distinction must be made between
hazard and risk. Hazard defines the inherent property of a chemical having
the potential to cause adverse effects when an organism, system or population
is exposed to that agent. Risk, however, establishes the probability of the
adverse effect occurring.
To be more specific, the risk of a chemical depends on the following 2
factors:
• The inherent toxicity of the chemical (hazard);
• How much of a chemical is present in the environmental medium
(e.g., water, soil, air) and how much contact a person or ecological
receptor has with the chemical substance (exposure).
A hazardous chemical substance poses no risk if there is no exposure. For
example, sulfuric acid is very corrosive. It is of no or negligible risk to
ordinary people who do not handle them. For some people who may be
exposed to sulfuric acid (scientists, workers), safety measures (i.e, wearing
goggles and gloves) are in place to minimize the risk.
In this newsletter, I will give you an introduction to chemical risk assessment.
However, the principles given in this article are consistent with risk
assessment methodologies for other sector uses such as pesticides and
cosmetics.

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C. Human Health Risk Assessment

Human health risk assessment is the process of analyzing information to
determine whether an environmental hazard might cause harm to exposed
persons. The risk-assessment process integrates many disciplines of
toxicology. It has both qualitative and quantitative components and consists
of four general steps: hazard identification, dose-response assessment,
exposure assessment, and risk characterization.
i. Step 1: Hazard Identification entails identifying the
substances/contaminants that are suspected to pose health
hazards, quantifying the concentrations at which they are
present in the environment, describing the specific forms of
toxicity (neurotoxicity, carcinogenicity, etc.) that the
substances/contaminants of concern can cause, and evaluating
the conditions under which these forms of toxicity might be
expressed in exposed humans.
ii. Step 2: Dose-Response Assessment entails further evaluating
the conditions under which the toxic properties of a chemical
might be manifested in exposed people, with particular
emphasis on the quantitative relationship between the dose
and the toxic response. The development of this relationship
may involve the use of mathematical models. This step may
include an assessment of variations in response—for example,
Vulnerability: differences in susceptibility between young and
old people or pregnant and non-pregnant, etc.
iii. Step 3: Exposure Assessment involves specifying the
population that might be exposed to the
substance/contaminants of concern, identifying the route(s)
through which exposure(s) can occur, and estimating the
magnitude, duration, and timing of the doses that people might
receive as a result of their exposure. This step requires the
exact understanding of product lifecycle, supply chain, end
users etc. The exposure to the population may be known (eg:
drugs consumed, cosmetics used) or unknown (through
contaminants) to the exposed population. In the scenarios
where exposure in unknown, the worst-case considerations of
exposure are used as a thumb rule.
iv. Step 4: Risk Characterization scientists combine information
from exposure assessments and toxicity assessments to
estimate the type and magnitude of risk faced by the exposed
population. This involves integrating information from the
first three steps to develop a qualitative or quantitative
estimate of the likelihood that any of the hazards associated
with the substance of concern will be realized in exposed
people. This is the step in which risk-assessment results are
expressed. Risk characterization should also include a full
discussion of the uncertainties associated with the exposure

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and toxicity assessments along with the in-depth justification

that may affect the outcome estimates of risk.

Toxicogenomic information has a potential role in all aspects of the risk-

assessment process. For example, in hazard identification, toxicogenomic
data could inform the types of hazard a chemical present (for example,
whether it poses cancer or noncancer risks) and the modes and mechanisms
of toxic action through which it acts. Information on the mode of action is
also a component in deciding the appropriate approach to dose-response
assessment (described further below). Toxicogenomic approaches could
support exposure assessment by indicating cellular exposure to toxicants.
Toxicogenomic data may also be used to better understand areas of
uncertainty, including variability in the human population, extrapolation of
data from one species to another, identification of susceptible subpopulations,
and provision of quantitative data to improve risk assessments.

D. Toxicity Assessment
Detection of toxicity requires a means to observe (or measure) specific
effects of exposures. Toxicology traditionally has focused on phenotypic
changes in an organism that result from exposure to chemical, physical, or
biologic agents. Such changes range from reversible effects such as transient
skin reactions to irreversible changes associated with chronic diseases, cancer
or even death. Typical whole-animal toxicology studies may range from
single-dose acute to chronic lifetime exposures, and they include assessments
of endpoints such as clinical signs of toxicity, body, and organ weight
changes, clinical chemistry, and histopathologic responses along with
assessment of absorption, distribution, metabolism, and excretion properties
in-order to establish systemic exposure to the substance.
Toxicology studies generally use multiple doses that span the expected range
from where no effects would be observed until clinical or histopathologic
changes would be evident. The highest dose at which no overt toxicity occurs
in a 90-day study (the maximum tolerated dose), is generally used to establish
animal dosing levels for chronic assays that provide insight into potential
latent effects, including cancer and reproductive or developmental toxicity.
These studies constitute the mainstays of toxicologic practice.
In addition to animal studies, efforts to identify and understand the effects of
environmental chemicals, drugs, and other agents on human populations have
used epidemiologic studies to examine the relationship between a dose and
the response to exposures. In contrast to animal studies, in which exposures
are experimentally controlled, epidemiologic studies describe exposure with
an estimate of error, and they assess the relationship between exposure and
disease distribution inhuman populations. These studies operate under the
assumption that many years of chemical exposures or the simple passage of
time may be required before disease expression can be detected.
As medical science has progressed, there are novel biomarkers and imaging
systems used to assess disease or toxicity. For example, more sensitive

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diagnostic and monitoring tools have been used to assess organ function,
including tools to detect altered heart rhythms, brain activity, and changes in
hormone levels as well as to analyze changes visible by electron microscopy.
Most notable, however, are the contributions of chemistry, molecular
biology, and genetics in detecting adverse effects as well as in identifying
cellular /molecular targets of toxicants. It is now possible to observe potential
adverse effects on molecules, subcellular structures, and organelles before
they manifest at the organismal level with the help of proteomics, genomics
and metabolomics techniques. This ability has enhanced etiologic
understanding of toxicity has made it possible to assess the relevance of
molecular changes to toxicity.
These molecular and cellular changes have been assessed and validated in
studies conducted on animals but have been applied to human populations
(“molecular epidemiology”) with some success. For example, our
understanding of gene-environment interactions has benefited greatly from
studies of lung, head, and neck cancer among tobacco users—studies that
examined differences in genes (polymorphisms) that are related to carcinogen
metabolism and DNA repair. Similarly, studies of UV sunlight exposure and
human differences in DNA repair genes have clarified gene-environment
interactions in skin cancer risk. Current technology now enables the role of
multiple genes of cell signaling pathways to be examined in human
population studies aimed at assessing the interplay between environmental
exposures and cancer risk.
Although current practice in toxicology continues to strongly emphasize
changes observable at the level of the whole organism as well as at the level
of the organ, the use of cellular and molecular endpoints sets the stage for
applying toxicogenomic technologies to a more robust examination of how
complex molecular and cellular systems contribute to the expression of
toxicity.

E. Quantification of Risk
The goal of chemical risk assessment is to have a full understanding of the
nature, magnitude, and probability of a potential adverse health or
environmental effect of a chemical. It considers both hazard and exposure.
Risk assessment forms the foundation of regulatory decisions for industrial
chemicals, pesticides, pharmaceuticals, cosmetics, food additives and food
contact substances in developed countries today.
Before proceeding to quantitative risk, let us learn some common
terminologies used in risk assessment:
i. Reference Dose (RfD): An estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily oral or dermal exposure to
the human population (including sensitive subgroups) that is likely to
be without an appreciable risk of deleterious effects during a lifetime.
Its unit is usually mg/kg bw/day or mg/kg.
ii. Reference Concentration (RfC): An estimate (with uncertainty
spanning perhaps an order of magnitude) of a continuous inhalation

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exposure to the human population (including sensitive subgroups) that

is likely to be without an appreciable risk of deleterious effects during
a lifetime. Its unit is usually mg/L or ppm.
iii. Point of Departure (POD) and How to Use It to Calculate
Toxicological Reference Dose (RfD):In toxicology, the point of
departure (POD) is defined as the point on a toxicological dose-
response curve established from experimental data or observational
data generally corresponding to an estimated low effect level or no
effect level. It marks the beginning of extrapolation to toxicological
reference dose RfDor reference concentration RfC. The most
common POD used to derive RfD is the no-observed-adverse-effect
level (NOAEL), lowest-observed-adverse-effect level (LOAEL), or
statistical benchmark dose (BMD).
iv. Threshold of Toxicological Concern (TTC) is a principle that refers to
the statistically established generic exposure level for all chemicals
below which there would be no appreciable risk to human health.
Once the threshold exposure level has been established, you simply
need to compare the actual/predicted exposure level with the
threshold value to determine if the relevant risk is acceptable or not.
The TTC approach has been used by regulatory authorities to assess
the risks of favoring substances, impurities in food and pesticide
metabolites. It is statistically derived threshold above which there is
minimal possibility of toxicity expected in the population. Eg, 1 in
10000 exposed population may be at risk of toxicity.
v. Why Is the Threshold of Toxicological Concern (TTC) Approach
Useful and Necessary? There are many synthetic and natural chemical
substances for which there are little or no toxicological data available.
They may be found in our products (i.e, food, cosmetics) or
environment (i.e, groundwater) either as constituents or impurities at
very low concentrations. It is not always possible to generate
toxicological data on them. To assess the risks of those substances, we
need an approach that does not require extensive toxicological data.
To address this problem, scientists have proposed the TTC approach.
It can be used for an initial assessment of a low-level substance to
determine whether a comprehensive risk assessment or additional
toxicology testing is required. TTC approach is also used to justify
non-threshold toxicities such as certain genotoxic mechanisms of
pharmaceuticals for which there is also lack of dose-response
relationship or lack of carcinogenicity data.
vi. Applicability of the TTC Approach: The TTC approach is not
intended to replace the risk assessment of regulated chemical
substances such as industrial chemicals, pesticide active ingredients or
food additives. It is primarily used to assess low-level substances such
as impurities and pesticide metabolites for which there is limited
toxicology data. Most of the times TTC is more conservative value
than the values derived from detailed risk assessment.

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In addition, the TTC approach is not applicable to high potency carcinogens

(i.e. aflatoxin-like, azoxy- or N-nitroso-compounds), inorganic substances,
metals and organometallics, proteins, steroids, substances that are known or
predicted to bioaccumulate, nanomaterials, radioactive substances, and
mixtures of substances containing both known and unknown chemical
structures.

i. Genotoxic Vs non-genotoxic carcinogenicity: Carcinogenicity can be

developed by the genotoxic or non-genotoxic mechanism of
carcinogenicity.

ii. Threshold-Dependent Genotoxicity: There are different mechanisms

in the development of mutagenicity. Some of the mechanisms are
threshold depended, while some mechanisms demonstrate
mutagenicity at any given dose of exposure. It is important to evaluate
substance for genotoxicity, and if positive it is important to know if
genotoxicity is threshold dependent. This information is crucial for
establishing controls. Non-threshold genotoxic carcinogens will
always be associated with the development of carcinogenicity, at any
dose or duration of exposure.

iii. Different analytical techniques are used in cancer and non-cancer risk
assessments to quantify risk. The result of a non-cancer risk
assessment can be the determination of a quantitative human
reference dose (RfD) for oral exposures or a reference concentration
(RfC) for inhalation exposures (both are generically referred to as a
“reference value”).

When developing a non-cancer reference value (RfD or RfC) for a chemical

substance, we survey the scientific literature and select a critical study and a
critical effect. The critical effect is defined as the adverse effect, or its known
precursor, that occurs at the lowest dose identified in the most sensitive
species as the dose rate of an agent increases. When a no-observed-adverse-
effect level (NOAEL) can be identified in a critical study, it becomes the
basis for the reference value derivation. If NOAEL cannot be identified, then
a lowest-observed-adverse-effect level (LOAEL) is identified instead.
Recently, benchmark doses (BMDs) from the modeling of dose-response data
have been used instead of the traditional NOAEL/LOAEL approach;
however, most RfDs are based on NOAELs. The NOAEL, LOAEL, or BMD
is divided by an appropriate uncertainty factor to derive the final reference
value. The uncertainty factors are generally 10-fold (but can be higher or
lower if informed by data) and are intended to account for uncertainty in the
available data as per
Table 1. Based on the application of the final reference value, toxicokinetic
and toxicodynamic uncertainty are considered. For carcinogenic compounds,
data from human epidemiologic studies are preferred, but, in the absence of

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human epidemiologic data, animal data is used. Dose-response curves are

constructed from these studies; however, the range of doses is frequently
above the levels of environmental interest. To estimate the risks below the
levels tested, the observed data are used to derive a point of departure
followed by extrapolation to lower exposures. Linear or nonlinear approaches
can be used to extrapolate to low doses, and the choice of methods is critical
because the derived risk estimates vary by technique. In general, linear
approaches produce more conservative risk estimates than nonlinear
approaches.
The selection of the various models used to extrapolate to low doses is
informed by a compound’s mode of action. The EPA cancer guidance states
that “when available data are insufficient to establish the mode of action for a
tumor site and when scientifically plausible based on the available data, linear
extrapolation is used as a default approach.” Further, “A nonlinear approach
should be selected when there are sufficient data to ascertain the mode of
action and conclude that it is not linear at low doses and the agent does not
demonstrate mutagenic or other activity consistent with linearity at low
doses.” For cancer risk assessments, extrapolations from the point of
departure can be used to calculate a cancer slope factor (for linear
extrapolation) and an RfD or RfC among other outputs (for nonlinear
extrapolation).
The values derived from cancer and non-cancer risk assessments are used to
protect the public from unacceptable chemical exposures and can be the basis
of regulatory decision making. These values have a range of implications to
stakeholders and, because of the uncertainty inherent in the risk assessment
process, their derivation can be quite controversial. As a result, tools such as
toxicogenomics that can be used in the risk-assessment process to increase
the certainty of risk estimates are of immense importance for protecting
public health.

iv. How to Use POD to Calculate RfD or RfC

RfD or RfC values can be calculated by dividing the point of departure (i.e,
chronic NOAEL or BMD) with corresponding uncertainty factors (UF).
When deriving acute reference dose (ARfD) is necessary, NOAEL from
short-term or single dose toxicity studies shall be used. In case of multiple
NOAELs for different effects and specifies, the lowest NOAEL value will be
chosen as the point of departure. Sometimes, you have to modify the point of
departure first before using the equation below.
𝑃𝑜𝑖𝑛𝑡 𝑜𝑓 𝐷𝑒𝑝𝑎𝑟𝑡𝑢𝑟𝑒 (𝑃𝑂𝐷)
𝑅𝑓𝐷 𝑜𝑟 𝑅𝑓𝐶 =
𝑈𝐹1 ∗ 𝑈𝐹2 ∗ 𝑈𝐹3 ∗ 𝑈𝐹4 ∗ 𝑀𝑜𝑑𝑖𝑓𝑦𝑖𝑛𝑔 𝐹𝑎𝑐𝑡𝑜𝑟 (𝑀𝐹)

Uncertainty factors and modifying factors are used to address the differences
between the experimental data and the human situation, taking into account
the following uncertainties in the extrapolation procedure.
• Interspecies differences
• Intraspecies differences

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• Differences in the duration of exposure

• Issues related to dose-response
• Quality of the whole database

Table 1 Standard uncertainty factors used by US EPA for risk assessment.

US EPA Uncertainty Factor (UF) for Risk Assessment Value

UF1 Accounts for variation in sensitivity among 10
human population
UF2 Accounts for uncertainty in extrapolation from 10
animal data to human
UF3 Accounts for extrapolation for sub-chronic to 10 (default is
chronic NOAEL (duration of the study/ exposure) 1)
UF4 Accounts to use of LO(A)EL or any other 10 (default is
endpoint as POD instead of NO(A)EL 1)
MF Additional uncertainty to account data quality 0<MF≤10
and confidence in data set (default is 1)

v. POD and RfD Example:

If 2 NOAEL values have been identified from long-term rat studies (10
mg/kg bw/day for reproductive toxicity, 50 mg/kg bw/day for dietary chronic
toxicity), the point of departure (POD) will be 10 mg/kg bw/day (the lowest
NOAEL). The derived RfD for human health effects will be 0.1 mg/kg
bw/day (10mg/kg bw/day divided by 100). If human exposure level to a
chemical substance by oral route is less than RfD 0.1mg/kg bw/day, the risk
of the substance is acceptable.

vi. When Is Modification of Point of Departure Necessary?

Modification of point of departure is necessary if there are any differences
between exposure routes and between experimental animals and humans.
• Differences in bioavailability (e.g., differences in absorption
between routes and between experimental animals and humans).
• Differences in the units of exposures in case of route-to-route
extrapolation (e.g., converting on oral NOAEL in mg/kg body
weight to inhalation NOAEC in mg/m3).
• Differences in human and experimental exposure conditions (e.g.
6hours/day for rat and 8hours/day for workers).
• Differences in respiratory volumes between experimental animals
(at rest) and humans (light activity).
It should be noted that modification is not appropriate in cases where the dose
descriptor is based on human data or where human exposure is evaluated
based on biological monitoring data.

vii. Which POD Is Better: NOAEL or BMD?

Both NOAEL and benchmark dose BMD can be used as the point of

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departure to derive RfD in USA or DNEL is EU. The BMD approach is now
EPA’s preferred approach and is fast becoming the world’s standard for dose-
response analysis. The BMD approach has distinct advantages over the
NOAEL approach in that the modeled benchmark dose (BMD05 or BMD10)
reflects the shape of the dose-response curve and is less affected by the
choice of experimental concentrations. However, the BMD approach requires
a robust dataset and additional knowledge of statistical modelling.
In our next tutorial, we will give you an introduction to the definition of
benchmark dose and how to use EPA's benchmark dose software (BMDS) to
calculate BMD05 and BMD10, which will later be used as the POD to derive
RfD values.

viii. How to Obtain Derived No- Effect Level (DNEL)?

Derived No- Effect Level (DNEL) is the level of exposure to the substance
above which humans should not be exposed. The DNELs are calculated by
dividing the value of the health effect dose descriptor (NOAEL, NOAEC,
LD50, LC50) by an assessment factor. Since dose descriptors are obtained
from experimental data, an assessment factor is required to allow for
extrapolation to real human exposure situations.
It may not always be possible to derive DNELs for each health effect. This
may be the case, for example, for carcinogenicity, where no safe threshold
level can be obtained. In these cases, a semi-quantitative value, known as the
DMEL or Derived Minimal Effect level may be developed.

ix. DNEL and Human Health Risk Assessment Example

Effects Adrenal Effects Developmental
Effects
NOAEL from the animal 30 mg/kg bw/day 80 mg/kg bw/day
study (oral route) (90day repeated
dose)
Assessment Factor 10 10
(Intraspecies)
Assessment Factor 10 10
(Interspecies)
Assessment Factor 3 1
(Duration)
Assessment Factor (Route 1 2
extrapolation, data quality)
Total Assessment Factor 10x10x3x1=300 10x10x1x2=200
(AF)
DNEL(oral route, long-term) 0.1mg/kg bw/day 0.4 mg/kg bw/day

In the above case, the DNEL used for risk characterization will be 0.1mg/kg
bw/day. If an adult (assuming weight is 60kgs) intakes 12mg of a chemical
substance per day, the estimated exposure (external dose per body weight)

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will be 0.2mg/kg bw/day. Since the exposure estimate is greater than DNEL,
which will lead to a Risk Characterization Ratio (RCR)>1, the risk will not
be acceptable.
x. How to Obtain Predicted No Effect Concentration (PNEC)?
The Predicted No Effect Concentration or PNEC is the concentration of a
substance in an environment below which adverse effects will most likely not
occur during a long term or short term exposure. The PNEC needs to be
determined for each environmental compartment (water, soil, sediment, etc.).
The PNEC for each environment is estimated by dividing the dose descriptor
by the relevant assessment factor. Since dose descriptors are obtained from
laboratory tests involving a limited number of species, the assessment factor
is required to account for the uncertainties involved in the extrapolation to the
real ecosystems.
Where several dose descriptors are available for an environment, all the
possible PNECs will be derived. The lowest PNEC will later be used for risk
characterization.
xi. PNEC and Environmental Risk Assessment Example
Compartment Eco-toxicology Dose Descriptors Assessme PNEC
nt Factor value

Surface water NOEC(Algae growth inhibition): 100mg/L; 10 1mg/L

NOEC(Daphnia reproduction):10mg/L;
NOEC (Fish chronic toxicity):20mg/L.
STP- 3h-NOEC>1000mg/L (activated sludge 10 100mg/L
microorganis inhibition test)
m

Soil LC50 (earthworm acute toxicity) >1000mg/kg 1000 1mg/kg

In the above case, PNEC-surface water is calculated as 1mg/L based on test

data on the most sensitive species (Daphnia). Let's assume that we discharge
wastewater containing 20mg/L of a substance directly to a river and the
dilution factor is 10, the Predicted Environmental Concentration (PEC-
water) will be 2mg/L. Since the RCR(equal to PEC-water/PNEC-water) is 2,
the risk is not acceptable. However, if we take some risk management
measures (i.e., oxidization, neutralization) to remove >60% of the substance
from wastewater before discharging, we will get an RCR less than 1 and
acceptable risks.
For other environmental compartments (sediment, soil, STP), we can do the
same risk characterization.
xii. The Cramer classification scheme (decision Toxtree): Toxtree is a
free QSAR tool that can be used to determine the Cramer class of a
chemical substance and estimate its relative toxic hazard. It is the
best-known approach to estimate the Threshold of Toxicological
Concern (TTC) for a chemical substance based on its chemical
structure. There are three Cramer classes with class III representing
the most severe toxic hazard. Class III chemical compounds are
assigned with the lowest TTC values.

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Cramer
Class
Description TTC
(µg/day*)
I Substances of a simple chemical structure with 1,800 (30
known metabolic pathways and innocuous end µg/kg
products which suggest a low order of oral toxicity. bw/day)
II Substances that are intermediate. They possess 540 (9
structures that are less innocuous than those in Class 1 µg/kg
but they do not contain structural features that are bw/day)
suggestive of toxicity like those in Class 3.
III Substances with chemical structures that permit no 90 (1.5
strong initial impression of safety and may even µg/kg
suggest a significant toxicity. bw/day)

What it means: For a chemical substance belonging to Cramer Class I, an

exposure level of less than 1,800µg/ day does not lead to unacceptable health
risks even if there is limited toxicology data about the substance. Assuming
the body weight of an adult person is 60kg, the threshold value can also be
written as 30µg/kg bw/day.
Note*: Above threshold values only apply to repeated dose toxicity,
reproductive and development toxicity. They do not apply to chemical
substances with structure alerts for mutagenicity or carcinogenicity.

F. Conclusion
Risk assessment is a complex process which depends on the quality of
scientific information that is available. It is best for assessing acute risks
where effects appear soon after exposure occurs. Uncertainty becomes
greater, the longer the period between exposure and appearance of symptoms.
This is due to greatly increased uncertainties in exposure assessment and the
problems involved in using epidemiological or laboratory animal results in
such cases. In many circumstances, these uncertainties make it impossible to
come to any firm conclusions about risk. Thus, risk assessment is a process
which is often useful but cannot always provide the answers that are needed.
Risk assessment is a complex subject difficult to cover in one short
newsletter. This first issue of the newsletter on risk assessment is just to
familiarize newer members of the toxicology community who are more used
to only conducting guideline studies but never had the opportunity to learn or
experience the risk assessment task.

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Questions
1. Define risk assessment?
2. The risk of a chemical depends on the 2 factors, ______and______
3. What are the steps involved in Human Health Risk Assessment?
4. Explain about Reference dose (RfD), Reference concentration (RfC),
Point of Departure (POD)?
5. Explain about Threshold of Toxicological Concern (TTC)?
6. Why is the Threshold of Toxicological Concern (TTC) approach useful
and necessary?
7. How to use POD to calculate RfD or RfC?
8. Write about Uncertainty factors and Modifying factors in risk
assessment?
9. When is modification of Point of Departure necessary?
10. Which POD is better: NOAEL or BMD?
11. How to obtain Derived No- Effect Level (DNEL)?
12. How to obtain Predicted No Effect Concentration (PNEC)?

-----------------------------------End of the Document----------------------------

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Basics of Chemical Risk Assessment