CHAPTER

Hazard and risk

assessment
6
CHAPTER OUTLINE
6.1 Introduction ....................................................................................................... 45
6.2 Risk Assessment Approach ................................................................................. 46
6.2.1 Preliminary Evaluation ......................................................................47
6.2.2 Toxicity Assessment..........................................................................47
6.2.3 Exposure Assessment........................................................................49
6.3 Conclusion ........................................................................................................ 51

6.1 INTRODUCTION
We often perform toxicological research to understand the mechanisms and
associated health risks following exposure to hazardous agents. The problem of
understanding the hazards and risks associated with unintentional or coincidental
exposures to chemicals is a complex one, with multiple uncertainties. Therefore,
risk assessment (RA) is a systematic scientific characterization of potential
adverse health effects following exposure to these hazardous agents. The RA
activities are designed to identify, describe, and measure qualities and quantities
from these toxicological studies, which are often conducted with homogeneous
animal models at doses and exposure durations not encountered in a more
heterogeneous human population.
Thus, the assessment of risks to human health involves the scientific
examination and evaluation of information in four areas: the hazardous nature of
agents in the environment; the degree of human exposure to such agents;
the response of people’s health to exposure; and risk management. The product of
a RA is information about the likelihood of health degradation following an
exposure to hazardous agents.
Risk Assessment (RA): RA can be defined as the systematic scientific evaluation
of potential adverse health effects resulting from human exposures to hazardous
agents or situations.
Risk is defined as the probability of an adverse outcome based on the exposure
and potency of the hazardous agent(s).

Fundamentals of Toxicology. DOI: http://dx.doi.org/10.1016/B978-0-12-805426-0.00006-8

© 2016 BSP Books Pvt. Ltd. Published by Elsevier Inc. All rights reserved.
45
46 CHAPTER 6 Hazard and risk assessment

RA requires an integration of both qualitative and quantitative scientific

information. For example, qualitative information about the overall evidence
and nature of the endpoints and hazards are integrated with quantitative assessments
of the exposures, host susceptibility factors, and the magnitude of the hazard.
A description of the uncertainties and variability in the estimates is a significant
part of risk characterization and an essential component of RA.

6.2 RISK ASSESSMENT APPROACH

Over the past several years, regulatory agencies in the United States have
developed a systematic scientific and administrative framework for RA. Major
regulatory agencies for the control and use of toxic chemicals and RA in the
United States are summarized in Table 6.1.
The functional elements for RA are well defined and widely accepted.
The factors and elements are important in the evaluation and have been
established by various regulatory agencies, including those in the United States.
Therefore, for risk analysis, the models used in RA may involve considerations
such as those provided in Table 6.2.

Table 6.1 Major Regulatory Agencies for Control and Use of Toxic Chemicals
and Risk Assessment in the United States
EPA: Air Pollutants Clean Air Act 1970
Water pollutants: Federal Water Pollution Control Act 1948
Drinking water: Safe Drinking Water Act 1974
Pesticides, Fungicides, Insecticides & Rodenticides Act (FIFRA) 1947
Food Quality Protection Act (FQPA) 1996
Ocean dumping: Marine Protection, Research, and Sanctuaries Act (MPRSA) and
Ocean Dumping Act (1972)
Toxic chemicals: Toxic Substances Control Act (TSCA) 1976
Hazardous wastes: Resource Conservation and Recovery Act (RCRA) 1976
Abandoned Hazardous Wastes Superfund (CERCLA) 1980
CEQ environmental impacts: National Environmental Policy Act (NEPA) 1969
OSHA: Workplace Occupational Safety and Health (OSH) Act 1970
Foods, drugs, and cosmetics (FDA): Food and Drugs Act 1906
Food, Drugs, and Cosmetics Act (FDC) 1938
FDA Modernization Act 1997
CPSC dangerous consumer products: Consumer Product Safety Act (CPSA) 1972
Transport of hazardous materials (DOT): Hazardous Materials Transportation Act (HMTA)
1975
EPA, Environmental Protection Agency; CEQ, Council for Environmental Quality (now Office of
Environmental Policy); OSHA, Occupational Safety and Health Administration; FDA, Food and Drug
Administration; CPSC, Consumer Product Safety Commission; DOT, Department of Transportation.
 6.2 Risk Assessment Approach 47

Table 6.2 Data Required for Preliminary Evaluation of Risk Assessment in

Human Health
Data Required Quality Data
Physiochemical processes Observed effects on humans
Toxicity Derived from animal studies
Release/transport/uptake Applicable to expected dosage
Chemical
physical interaction Most current to support specific conclusions

Physiochemical processes include the following:

1. Human reactions to hazard exposure
2. Population demographics
3. Animal or human similarity or dissimilarity
4. Industrial control pollution methods

6.2.1 PRELIMINARY EVALUATION

Chemicals are normally classified as hazardous or toxic based on the results of
animal studies that are then extrapolated to humans. Toxicity may be established
without such observations based on experience with similar chemicals/or materials.

6.2.2 TOXICITY ASSESSMENT

The main evidence used in an assessment of toxicity comes from two sources:
1. Human studies (epidemiological studies)
2. Animal studies
Some supporting information may be obtained from clinical and in vitro studies.
Thus, the risk approach identifies the following four major elements of RA.
The information developed in the RA process is utilized in risk management, and
decisions are made regarding the need for and the degree of steps to be taken to
control exposures to the chemical of concern (Fig. 6.1).
1. Hazard identification
a. Epidemiology
b. Animal studies
c. Short-term assays
d. Structure
activity relationship
2. Exposure assessment
a. Identification of exposed populations
b. Identification of routes of exposure
c. Identification of degree of exposure
48 CHAPTER 6 Hazard and risk assessment

FIGURE 6.1
The four major elements of risk assessment. The information developed in the risk assessment
process is utilized in risk management, whereby decisions are made based on the need for
and degree of the steps that should be taken to control exposures of chemicals of concern.
Source: NRC, 2007. Models in Environmental Regulatory Decision Making. The National Academies Press,
Wasington, DC. Available at: http://www.nap.edu/read/11972/chapter/4.

3. Dose
response assessment
a. Quantitative toxicity information collected
b. Dose
response relationship established
c. Extrapolation of animal data to humans
4. Risk characterization
a. Estimation of the potential for adverse health effects to occur
b. Evaluation of uncertainty
c. Summarization of risk information
In principle, carefully performed epidemiological studies can provide very
convincing evidence about a possible relationship between a toxicant and a
disease. Because animals are not humans, care must be taken in extending such
results to human conditions. When possible, multiple species should be involved
in animal tests to minimize the effects of interspecies differences.
 6.2 Risk Assessment Approach 49

The data obtained from various experiments are separated into those that do
not increase the likelihood of cancer and those that do. For noncancer-related end
points, the concept of no observed adverse effect level (NOAEL) is applied.
As described in previous chapter, approaches for characterizing dose
response
relationships include identification of effect levels such as LD50 (dose producing
50% lethality), LC50 (concentration producing 50% lethality), ED10 (dose
producing 10% response), and NOAELs. NOAELs have traditionally served as the
basis for RA calculations, such as reference doses or acceptable daily intake (ADI)
values. Reference doses (RfDs) or concentrations (RfCs) are estimates of daily
exposure to an agent that is assumed to be without an adverse health impact in
humans. The ADIs are used by WHO for pesticides and food additives to define
“the daily intake of chemical, which during an entire lifetime appears to be without
appreciable risk on the basis of all known facts at that time.” Reference doses and
ADI values typically are calculated from NOAEL values by dividing by uncertainty
factor (UF) and/or modifying factors (MF). Tolerable daily intake (TDI) can be
used to describe the intake of chemicals that are not “acceptable” but are “tolera-
ble” because they are below levels thought to cause adverse health effects. These
are calculated in a manner similar to that for ADI. In principle, dividing by the
uncertainty factors allows for interspecies (animal-to-human) and intraspecies
(human-to-human) variability with default values of 10 each. An additional
uncertainty factor is used to account for experimental inadequacies, for example, to
extrapolate from studies with short exposure to a situation more relevant for chronic
study or to account for inadequate numbers of animals or other experimental limita-
tions. If only a LOAEL value is available, then an additional 10-fold factor is com-
monly used to arrive at a value more comparable to a NOAEL value. Traditionally,
a safety factor of 100 is used for RfD calculations to extrapolate from a well-
conducted animal bioassay (10-fold factor, animal-to-human) and to account for
human variability in response (10-fold factor, human-to-human variability).
An assumption is made that exposure below a certain level, the NOAEL, will
have no adverse health consequences. An acceptable reference dose, RfD, is then
established by:
RfD 5 NOAEL=ðUF 3 MFÞ
ADI 5 NOAEL=ðUF 3 MFÞ
where the uncertainty factor (UF) is typically equal to 100 and MF is the
modifying factor.
For cancer end points, the only strictly safe exposure level is at zero dose, although
for very small doses the risk is extremely low and is not considered significant.

6.2.3 EXPOSURE ASSESSMENT

Estimation of exposure begins with the detailed description of the toxic agent.
In circumstances where exposure has already occurred, it is easy to obtain
50 CHAPTER 6 Hazard and risk assessment

sufficient information to make an assessment of the exposure. Due to lifestyle

changes in the population, long-term modeling becomes difficult. However, it
helps the expert to estimate the dose input for a human subject.
Therefore, the primary objectives of the exposure assessment are to determine
the source, type, magnitude, and duration of contact with the chemical of
interest. Risk Commission frameworks for risk assessment and risk management
provide a consistent framework-based approach for evaluating risks and taking
action to reduce risks. The objectives of risk assessments vary with issues, risk
management needs, and statutory requirements. Hence, toxicology, epidemiology,
exposure assessment, and clinical observations can be linked with biomarkers,
cross-species investigations of mechanisms of effects, and systematic approaches
to risk assessment, risk communication, and risk management. Conceptually,
calculations are designed to represent a “plausible estimate” of the exposure of
individuals in the upper 90th percentile of the exposure distribution. Upper-bound
estimations would be “bounding calculations” designed to represent exposures at
levels that exceed the exposures experienced by all individuals in the exposure
distribution and are calculated by assuming limits for all exposure variables.
For example, risk calculations of arsenic (As) exposure via a soil ingestion route
is calculated using point estimates, and a lifetime average daily dose (LADD) is
calculated as follows:
Concentration of toxicant in exposure media 3 Contact rate 3
Contact fraction 3 Exposure duration
LADD 5
ðBody weightÞ ðLifetimeÞ

Many exposures are now estimated using exposure factor probability

distributions rather than single-point estimates for the factors within the LADD
equation. In general, estimates for cancer risk use average exposure over a lifetime
(see previous LADD example). In a few cases, short-term exposure limits (STELs)
(eg, ethylene oxide) and characterization of brief but high levels of exposure are
required. In these cases, exposures are not averaged over the lifetime and the
effects of high, short-term doses are estimated. With developmental toxicity, a
single exposure can be sufficient to produce an adverse developmental effect;
therefore, daily doses are used rather than lifetime weighted averages.
There is a great concern about involuntary exposures (especially in the food
supply, drinking water, and air) and unfamiliar hazards, such as radioactive waste,
electromagnetic fields, asbestos insulation, and genetically modified crops and
foods.
In brief, the hazard and RA is based on four components: hazard identifica-
tion, research, risk assessment, and risk management. The approach is based on
uncertainty and the use of various mathematical models while keeping in mind
the public health concern and the economic, social, and political contexts for risk
management options. Such decisions are made by a risk management group.
The details of the models used and the recent approach of the “benchmark dose”
are beyond the scope of this chapter.
 6.3 Conclusion 51

6.3 CONCLUSION
As scientists, we must clearly communicate the uncertainty associated with our
extrapolations; otherwise, we are being dishonest. Our most vigorous efforts must
be focused on those activities that best allow us to address these problems. These
studies should include designing better studies from the perspective of RA, that
is, they should cover a broader range of doses with a focus on the molecular and
cellular mechanisms. Advances in toxicology are certain to improve the quality of
risk assessments, to find substitute data for assumptions, and to help describe the
models with more credibility.