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ENVIRONMENT & HEALTH BACKGROUND REPORT
November 1995
Vol. 1., No. 2
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Background information for science, health,
and environmental reporters
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RISK ASSESSMENT: CLAIMING TO ESTABLISH ‘SAFETY’
I. The Source:
Anna Fan, Robert Howd, and Brian Davis, “Risk Assessment of
Environmental Chemicals,” ANNUAL REVIEW OF PHARMACOLOGY AND
TOXICOLOGY Vol. 35 (1995), pgs. 341-368. The Annual Review of
Pharmacology and Toxicology is published by Annual Reviews,
Inc., 4139 El Camino Way, Box 10139, Palo Alto, CA 94303-0139.
Editor: Arthur K. Cho; telephone: (415) 493-4400. Annual
subscription rate: $47 ($52 foreign).
[NOTE: Risk assessment is widely used by government and industry
to set “safe” levels for chemical exposures to workers and to
the general public. Many dangerous technologies — pesticides,
medical waste incinerators, and soil-burning incinerators, for
example — are promoted as ‘safe’ based on risk assessments that
evaluate the chemicals emitted and deem their risks
‘acceptable.’ It is therefore important to understand what risk
assessment is, how it works, and what its shortcomings may be.
It is not a simple topic, but an exceedingly important one. The
“source” article this month is long and complex, but it
describes the critical components of a risk assessment, thus
preparing readers to ask good questions the next time a risk
assessment comes their way.–P.M.]
II. Salient Facts from the Source:
[In the summary below, I have added explanations inside square
brackets, attempting to clarify the text.–P.M.]
Risk assessment is an evolving process based mainly upon
toxicology, but it is also based upon a broad background of
knowledge in other fields: chemistry, physiology, molecular
biology, environmental transport processes [how chemicals move
through the environment], and applied statistics.
Risk assessment has been defined by the National Academy of
Sciences as a four-step process:
Step 1: Hazard identification.
Hazard identification involves estimating chemical risks for
acute (single dose), subchronic (a few doses), or chronic
exposures for each possible toxic endpoint, such as liver damage
[or birth defects, or immune system damage, or central nervous
system damage, or reproductive system damage, or cancer, and any
other such “endpoint”].
Step 2: Dose-response assessment.
Dose-response assessment usually includes extrapolation from high
doses to low doses. [Dose-response assessment means determining
what damage, and to which bodily systems, will occur as the dose
of a chemical increases. Most people are familiar with the
concept of dose-response; think of the effects from drinking one,
two, or three glasses of wine. In general, greater dose leads
to greater effect. To extrapolate means to project or extend
known data into an area not known so as to arrive at knowledge,
which is usually conjectural. Ethical considerations, embodied
in the Nuremberg principle, established in international law
after W.W. II, prevent testing of toxic chemicals on humans.
Therefore, laboratory animals are tested instead. Because the
number of animals tested is small, high doses are usually
administered in the hope that, if there is a subtle effect from a
chemical, it will be discerned even though the test group is
small. As a result, laboratory animal findings must be
extrapolated from the high doses given in the lab to the much
lower doses to which humans would be exposed through contact
with chemicals in the environment.]
Starting with information about the effects of high doses on
various species of laboratory animals, many different techniques
and models are used to estimate what the effects of low doses on
humans might be.
Step 3: Exposure assessment.
Exposure assessment attempts [or should attempt] to determine how
much of a chemical (or of all similar chemicals) is absorbed
from all sources. Example: if the chemical is a pesticide,
exposures might occur through food, groundwater, air, and
through home and occupational uses.
Step 4: Risk characterization.
This final step in a risk assessment uses data from the three
previous steps to make decisions regarding individual and
population risks, blending the previous steps with information
about the characteristics of the exposed population to describe
the potential adverse outcomes and to describe the strength
[validity] of both the evidence and the extrapolations. [In
other words, the authors are saying that risk characterization
takes information from hazard assessment, dose-response
assessment, and exposure assessment, then adds information about
the characteristics of the affected population — How old are
they? Do they eat a lot of fish? Are they generally
malnourished or overweight? — and combines it all together to
determine an estimate of risk, usually expressed as a probability
of a particular kind of harm over a specified period of time.
For example, a typical estimate of risk might be expressed this
way: a particular group of people is expected to endure one
additional cancer for every 10,000 people, over and above the
normal risk of cancer, as a result of chronic exposure to some
toxic chemical in their drinking water during their lifetime of
70 years.]
The four components of risk assessment are carried out roughly in
the order given, leading toward a quantitative estimate of the
relative risk of a chemical exposure under specified conditions.
This review [the source article] addresses several areas of risk
assessment that are receiving heightened attention, including
neurotoxicity, immunotoxicity, reproductive and developmental
toxicity, genotoxicity, carcinogenicity, and toxicokinetics
[details of how toxicity occurs within the cells of bodily
systems] and modeling [making mathematical approximations of
physical, chemical and biological processes].
“Risk assessment is an evolving art based on sound scientific
principles and judgments….”
“Not all considerations in risk assessment are specified in any
one set of laws or procedural manuals; many are built upon the
training and experience of the toxicologists who assess the
risk. Thus there may be significant variations in the conduct
and results of risk assessments.”
General toxicity considerations
Protecting the public from toxic effects of environmental
chemicals primarily involves considering the mechanisms of
toxicity at low exposure levels, and likely biological effects
from such exposures. Potential cumulative, irreversible effects
such as carcinogenesis and neurotoxicity receive the most
attention. Developmental effects are also intensively
investigated, because a single exposure during a sensitive
period in gestation [gestation is the time from conception to
birth] can have lifelong detrimental effects. Preventing
exposure to mutagens is important for the same reason.
[Emphasis added; we return to this point below. Mutagens are
toxins that can damage the genes, sometimes causing cancer or
other illnesses in the affected person, but also sometimes
causing damage that may be inherited by the person’s offspring.]
In the study of problems other than cancer, the goal is to
protect an exposed human population against any adverse effects
by estimating a safe dose level, called a reference dose. The
“safe” or “reference” [sometimes called “rfd”] dose is
calculated as follows: The highest dose that doesn’t cause
toxicity (the no observed effect level, or NOEL) or, if that is
unavailable, the lowest dose observed to have a toxic effect
(the lowest observed effect level, or LOEL) in an animal study is
divided by safety or uncertainty factors. [In other words,
scientists take what they think are ‘safe’ levels for animals
and they divide it, thus making it even smaller, and call it a
“safe’ dose for humans.]
In calculating the reference dose, safety factors of ten have
commonly been applied to account for (a) uncertainty caused by
extrapolation between species [for example, from rats to
humans], for (b) variations in sensitivity among humans, for (c)
extrapolation from a LOEL to a NOEL (when necessary), and for
(d) estimating a safe chronic dose when only acute or subchronic
toxicity levels are known. The total uncertainty factor used
may thus vary from 10 to 10,000, depending on the available data;
the most common value is 100. [In other words, in the typical
case, a ‘safe’ dose is determined for, say, a rat, and that dose
is divided by 100 to establish a ‘safe’ dose for a human.]
Uncertainty factors are used to account for both the inherent
variability in humans (e.g. individual differences in size, age,
exposure, metabolic rate, disease states, genetic
susceptibility, etc.) and uncertainty resulting from undefined
[unknown] toxic effects. “Some uncertainty may remain
unquantifiable,” the authors say.
Exposure to multiple chemicals
“Because of the near-infinite number of potential mixtures, it is
impossible to experimentally test for all interactions, and
relevant studies of an effect or interaction [between multiple
chemicals] are not usually available.”
Neurotoxicity assessment
Comprehensive evaluation of neurological competence [health of
the central and peripheral nervous systems] is difficult and
expensive. Dozens of procedures to analyze various nervous
system functions have been developed over the last few decades
to evaluate both acute and chronic effects of chemicals, but no
comprehensive test battery has emerged as a standard.
“Information on neurotoxicity for most environmentally
significant chemicals is therefore fragmented and difficult to
interpret, and there are no simple guidelines for use of the data
in risk assessment.” The US EPA [Environmental Protection
Agency] has been in the process of formulating neurotoxicity
[testing] guidelines for several years [but has not finalized
those guidelines.]
Immunotoxicity testing
Risk assessment of immunotoxic chemicals is a new and challenging
area. Reasons for its significance include:
(a) recent emphasis on the human health implications of the
immune system; (b) public awareness that chemicals or biological
agents can alter immune responses, as seen in acquired immune
deficiency syndrome (AIDS); (c) the ability of immune function
tests to detect changes at very low doses; (d) the fact that
pesticides, a major class of chemicals, are known to modulate
[modify] immune system response; (e) special vulnerability to
immune system distress among young, old, pregnant, and
malnourished individuals; (f) the potential for development of
hypersensitivity, including Multiple Chemical Sensitivity (MCS);
[MCS is a poorly-understood, and therefore controversial,
disorder in which patients complain of a wide range of symptoms
after exposure to low levels of chemicals that give off odors,
such as perfumes, new carpets, etc.]; (g) and the current lack
of regulatory data requirements and risk assessment guidance for
immunotoxic effects.
Impaired immune response can result in increased susceptibility
to, or decreased resistance to, bacterial, fungal, and viral
infections, and to some forms of cancer.
The immune system is a complex network of lymphoid organs [lymph
system] and cells in circulating blood and elsewhere in the body
which interact to generate the immune responses. No single test
is adequate to measure the immunologic effects of chemicals on
those multiple system components.
It is reasonable to suppose that significant immunologic changes
in exposed individuals will produce adverse outcomes. This
concept is supported by human data from individuals with genetic
or virus-induced (e.g., AIDS) immunodeficiencies and from those
being therapeutically immunosuppressed (e.g., organ transplant
recipients). [In other words, there is evidence from human
experience that people tend to get sick when their immune
systems are damaged.] In addition, a good correlation between
immune test results and altered host resistance has been
demonstrated in animal studies. [In other words, data from
animal studies confirm that a damaged immune system can give
rise to disease.]
To date, little immunotoxicity information is available for
environmental chemicals. In the US EPA Integrated Risk
Information System (IRIS), which provides summary toxicity data
on over 200 chemicals, only one chemical has a reference dose
based on immunotoxicity. The National Academy of Sciences in
its recent study of pesticides in the diets of infants and
children, recommended immunotoxicity assessment as part of a
complete pesticide safety evaluation. Regulatory agencies such
as the US EPA and the US FDA [Food and Drug Administration] are
developing testing guidelines and data requirements for
immunotoxicity testing. Formal guidelines for the use of
immunotoxicity data in risk assessment do not exist.
Developmental toxicity assessment
Developmental toxicity is toxicity that adversely affects
offspring through maternal exposure, with effects becoming
apparent during the period from birth to sexual maturity.
Adverse developmental effects include structural abnormalities,
growth alteration, functional defects, and death. The most
common test for developmental toxicity involves exposing
females, typically rodents and rabbits, to a toxic chemical in
the air, water or diet at various stages of pregnancy. By
limiting exposure to various stages of gestation, it is possible
to define the period of development that is most vulnerable.
Reproductive toxicity assessment
Reproductive toxicity is toxicity that adversely affects any
aspect of male or female reproductive function. Effects may be
observed as changes in reproductive cells or organs, in
endocrine functions, or in behavior. [The endocrine system
regulates bodily functions, including growth, development, and
sexual characteristics, via hormones.] Because they affect
reproductive cells, (germ line, meiotic cells, or gametes),
genotoxic effects may be included in reproductive toxicity.
[When they divide, meiotic cells give rise to gametes; germ line
and gametes are sex cells, i.e., sperm cells or female egg
cells, damage to which can be inherited by the offspring.] A
mutational event in such a cell could theoretically be caused by
a single molecule [of a toxic chemical]. This possibility is
the basis for assertions that some development and reproductive
toxins are non-threshold agents. [Non-threshold agents are
harmful chemicals for which there is no threshold, no dose below
which damage will not occur; for non-threshold agents, the only
completely ‘safe’ dose is zero.]
Reproductive toxicity can be assayed [assessed, or tested] in a
two-generation rodent study.
In pregnant women, adverse affects may occur in the fetus at dose
levels too low to affect the mother, because the fetus is more
sensitive to certain effects. Adverse fetal affects that occur
at dose levels below those that cause maternal toxicity are
clearly of concern. A recent study by the National Academy of
Sciences [PESTICIDES IN THE DIETS OF INFANTS AND CHILDREN
(Washington, D.C.: National Academy Press, 1993)] assumes that a
safety factor of 1000 below the mother’s NOEL may be necessary
to protect the fetus.
Genetic toxicity (genotoxicity) assessment
Risk assessment for genetic effects is both important and
difficult. The outcome of 5-10% of live human births is a
significant birth defect. It has been estimated that among all
congenital effects [birth defects] about 20% have environmental
causes, 20% have predominantly genetic causes, and 60% result
from a combination of the two. [In other words, environmental
factors contribute to 20% + 60% = 80% of all birth defects.
There were 4.1 million live births in the U.S. in 1993, according
to the 1994 edition of the Statistical Abstract of the United
States.]
In addition to problems that are severe enough to be recognized
as birth defects, genetic changes can lead to more subtle
results: a child may lead a less healthy life, be more
susceptible to disease, or have a shortened productivity and life
span.
A major problem in hazard identification is to determine the
relevance to human health of the hundreds of available
genotoxicity assays [tests].
Animal assays for germ line mutations [inheritable mutations] are
costly and difficult, while human germ line data are never
available.
Direct chemical interactions with genes represent non-threshold
phenomena. [In other words, the only safe dose is zero.]
The US EPA has developed guidelines for mutagenicity risk
assessment and in a series of papers has attempted to
demonstrate appropriate risk assessment procedures, using
ethylene oxide as an example. These results were offered in
order to stimulate discussion and progress in this area, but a
consensus on genetic risk assessment is not yet in view. [In
other words, there is no agreed-upon way of assessing genetic
risks, for the purposes of risk assessment, and agreement on
such methods is unlikely to be reached soon.]
Carcinogenicity assessment
Risk assessments evaluate carcinogenicity differently from other
toxic effects. The primary reason for this is the treatment of
carcinogenicity as having no threshold and all other toxicity as
having a threshold. The basis for this hypothesis is that
mutations in a few critical genes can lead to the loss of
regulation of cell division. Thus a few molecules of a
carcinogen can produce an unregulated cell that divides to form
a clone [an identical twin cell, which then divides to form two
more identical cells, and so on] and ultimately a tumor composed
of unregulated cells. [In other words, if a cell loses the
ability to regulate itself, i.e., to stop growing, it can
eventually form a cancer.] The consequence of this assumption
is that any dose of a carcinogen, no matter how small, should
produce a calculable risk. [In sum, carcinogens are assumed to
be non-threshold toxins.]
Genotoxic chemicals should also lack a threshold, but because of
the difficulties in risk assessment described in the previous
section, they are not evaluated in the same manner nor with the
same concern as carcinogens.
Carcinogens are regulated at risk levels in the range of 1 X 10-4
(one in 10,000) to 1 X 10-6 (one in a million). Such levels are
based on rodent studies with about 50 males and 50 females in
each dose group. Because male and female outcomes are treated
separately, the limits of resolution for these assays are on the
order of a few percent for a response. [In other words, because
the size of the test group is small, such a test can only
discern gross effects — effects that occur in several percent of
the tested animals. If an effect were to occur in only one in
10,000 animals or one-in-a-million, such tests would not be able
to discern that effect.]
III. Our Interpretation:
This article was written by qualified scientists who are
enthusiastic about risk assessment and who use it regularly in
their work for the California Environmental Protection Agency
(Cal EPA).
Nevertheless, the article highlights major shortcomings of risk
assessment. For example:
Risk assessment is not really a science; it is an art that weaves
together various strands of information, some of which have been
gathered by scientific methods. The authors say risk assessment
is “an evolving art based on sound scientific principles and
judgments….” But “judgments” are not scientific because they
are not reproducible from one laboratory to another; different
risk assessors will make different judgments when faced with the
same data (or the same lack of data).
Yet risk assessment is routinely characterized in the media and
elsewhere as a scientific enterprise — a characterization that
is misleading at best, and intentionally deceptive at worst.
The authors acknowledge that different risk assessors will reach
different conclusions because risk assessments are completed
using differing techniques: they say, “Not all considerations in
risk assessment are specified in any one set of laws or
procedural manuals; many are built upon the training and
experience of the toxicologists who assess the risk. Thus there
may be significant variations in the conduct and results of risk
assessments.” Here we see again that risk assessment is not a
science, but an art.
Risk assessment has traditionally emphasized the carcinogenicity
of chemicals. But as the authors point out, there are many
kinds of harm that chemicals can cause besides cancer. A risk
assessment needs to consider neurological damage; damage to the
immune system and the endocrine system; developmental damage;
reproductive damage; and genetic damage.
They say, for example, “Developmental effects are also
intensively investigated, because a single exposure during a
sensitive period in gestation can have lifelong detrimental
effects. Preventing exposure to mutagens [chemicals that cause
inheritable genetic changes] is important for the same reason.”
In other words, a single exposure to a toxic chemical at the
“wrong time” during development can cause permanent damage to a
fetus or a young animal or child.
There will always be aspects of the toxicity of a chemical that
are not known, so “uncertainty factors” will be applied to try
to protect public health from unknown hazards. The authors say,
“The total uncertainty factor used may thus vary from 10 to
10,000, depending on the available data; the most common value is
100.” But, the authors say, “Some uncertainty may remain
unquantifiable.” If uncertainties cannot be quantified, then
one cannot know whether a safety factor of 10 or 100 or 1000 is
“adequate” to protect public health and safety. One can guess
and hope, but guesswork and hope are not science — they belong
in the realm of art or personal philosophy.
The effects of multiple exposures cannot be known: The authors
say, “Because of the near-infinite number of potential mixtures,
it is impossible to experimentally test for all interactions,
and relevant studies of an effect or interaction are not usually
available.” So risk assessors study the effects of one chemical
at a time, as if people and animals were never exposed to
multiple chemicals simultaneously. This is a major flaw in
decision-making that is based upon risk assessment. In the real
world, people are exposed to multiple chemicals all the time —
prescription drugs, cigarette smoke, automobile exhaust,
multiple pesticides, food additives, indoor air pollution from
building materials, carpets, and so on.
The likelihood of nervous system damage cannot be reliably
evaluated because there is no standard way to test for it: The
authors say, “Dozens of procedures to analyze various nervous
system functions have been developed over the last few decades
to evaluate both acute and chronic effects of chemicals, but no
comprehensive test battery has emerged as a standard.
Information on neurotoxicity for most environmentally
significant chemicals is therefore fragmented and difficult to
interpret, and there are no simple guidelines for use of the
data in risk assessment.”
The likelihood of damage to the immune system cannot be reliably
evaluated because, as the authors say, “No single test is
adequate to measure the immunologic effects of chemicals on
those multiple system components.” And, they say, where data do
exist, the meaning of the data is not clear: “Human data
concerning chemically induced modulations [modifications] of
immune-response parameters are scarce. Where modulations have
been observed, the biological significance has been unclear.”
Furthermore, immune system toxicity data are truly scarce: The
authors say, “To date, little immunotoxicity information is
available for environmental chemicals. In the US EPA Integrated
Risk Information System (IRIS), which provides summary toxicity
data on over 200 chemicals, only one chemical has a reference
dose based on immunotoxicity.” There are over 60,000 chemicals
currently in commercial use, so having ‘safe’ doses established
for only one chemical based on immune system toxicity gives an
indication of how far we have to go.
Toxicity to human genes is important, but difficult to assess.
As the authors say, “Developmental effects are also intensively
investigated, because a single exposure during a sensitive
period in gestation can have lifelong detrimental effects.
Preventing exposure to mutagens is important for the same
reason.”
The authors say, it has been estimated that among all congenital
effects [birth defects] about 20% have environmental causes. In
other words, environmental factors alone cause 20% of all birth
defects. There are about 4 million live births each year in the
U.S., so there are between 200,000 and 400,000 serious birth
defects each year. Of these, 40,000 to 80,000 are caused by
environmental influences and not by inherited genetic problems,
according to the authors.
In addition to problems that are severe enough to be recognized
as birth defects, genetic changes can lead to more subtle
results: a child may lead a less healthy life, be more
susceptible to disease, or have a shortened productivity and life
span.
There is no way to quantify such subtle effects, and no way to
avoid them except by eliminating exposures to genotoxic
chemicals. Risk assessment thus gives a false sense of
security.
But genotoxic chemicals are very difficult to identify: The
authors say, “A major problem in hazard identification is to
determine the relevance to human health of the hundreds of
available genotoxicity assays [tests].
“Animal assays for germ line mutations [inheritable mutations]
are costly and difficult, while human germ line data are never
available,” the authors say.
“Direct chemical interactions with genes represent non-threshold
phenomena,” the authors say. [In other words, the only safe
dose is zero; if a large population is exposed to a
non-threshold chemical, some damage will occur, even at low
doses.]
“…a consensus on genetic risk assessment is not yet in view.”
[In other words, there is no agreed-upon way of assessing
genetic risks, for the purposes of risk assessment, and
agreement on such methods is unlikely to be reached soon.]
Therefore, it seems proper to conclude that testing of chemicals
for genotoxicity is very important, but cannot be done at
present, and is unlikely to be done in the near future.
Furthermore, it is known that some chemicals can harm the nervous
system, but risk assessors have no standard way to evaluate
chemicals for such damage.
Furthermore, it is known that some chemicals can harm the immune
system, but risk assessors have no standard way to evaluate
chemicals for such damage.
Furthermore, it is known that humans are exposed to multiple
chemicals simultaneously, but risk assessors have no way to
evaluate the effects of several chemicals simultaneously.
Furthermore, the authors have presented evidence that
developmental toxicants, reproductive toxicants, and genetic
toxicants are all non-threshold chemicals. Carcinogens are also
considered to be non-threshold chemicals. For these classes of
hazardous chemicals, the only safe dose is zero, which means we
must prevent exposures not rationalize and justify them via risk
assessment.
And lastly, in our 25 years of experience advising citizen
groups, we have never seen a risk assessment that conforms to
the guidelines implied in this article. For example, we have
never seen a risk assessment that actually took into account the
particular characteristics of an exposed population; “averages”
are used, not particulars. Therefore, though this article
defines a risk assessment as a rather thorough investigation, in
our experience, the “rules” for carrying out risk assessments are
more honored in the breach than in the observance.
In sum, risk assessment is not a technique that can protect the
public from toxic chemicals. Instead, it is a technique that
gives the public a false sense of security, while allowing
health damage to occur. People, including scientists, who claim
to be able to determine ‘safe’ doses of chemicals based on risk
assessment techniques are deceiving themselves and — worse —
misleading the public.
IV. Contacts:
Anna Fan, senior author, is chief of the Pesticides and
Environmental Toxicology Section, Office of Environmental Health
Hazard Assessment, California Environmental Protection Agency:
(510) 540-3063.
Robert Howd is a staff toxicologist with the Pesticides and
Environmental Toxicology Section, Office of Environmental Health
Hazard Assessment, California Environmental Protection Agency:
(510) 540-3063.
Brian Davis is with the Office of Scientific Affairs, Office of
Toxic Substances Control, California Environmental Protection
Agency: (916) 327-2493.
Mary O’Brien is staff scientist with Environmental Research
Foundation; she lives in Eugene, Oregon, where she can be
reached at (503) 485-6886. O’Brien is writing a book
criticizing society’s excessive reliance on risk assessment for
decision-making, and proposing that we evaluate all available
alternatives before making decisions–a simple change with
far-reaching ramifications.
ENVIRONMENT & HEALTH BACKGROUND REPORT is published monthly
by Environmental Research Foundation, P.O. Box 5036,
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ENVIRONMENT & HEALTH BACKGROUND REPORT is to provide
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