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OCR for page 19
if
Chemical Contaminants:
Safety And
Risk Assessment
The hazards of ingesting pollutants in drinking water can be assessed in
two general ways: with studies of toxicity in the laboratory and with
epidemiological studies. Studies in the laboratory may employ a variety
of experimental systems, ranging from chemical ejects of pollutants on
DNA, through exposure of bacterial or mammalian cells in culture, to
lifetime feeding studies on experimental animals. They are prospective
studies, in which relatively small numbers of cells or animals are exposed
to characterized pollutants at known concentrations. Epidemiological
studies deal with human populations. Their design is constrained by
external circumstances, and they involve large numbers of people whose
exposure to the pollutant in question is commonly uncertain and
confounded by exposure to other pollutants.
The aim of studies of both types is to allow the risk to man to be
estimated. The first can give precise information on relatively high risks
related to individual pollutants in this or that animal species to which
human exposure and risk may be compared. The second can provide less
precise information on the human risk related to one pollutant (isolated,
it is hoped, from other pollutants).
Toxicity data obtained from laboratory animals will generally have to
be relied on for estimating human risk, if we are to control human
exposure to carcinogens. Epidemiological studies have discovered causes
of disease and can buttress, supplement, or contradict laboratory data.
Imaginative comparisons between laboratory and epidemiological data
19
OCR for page 20
20 DRINKING WATER AND H"LTH
are of the utmost importance, particularly in the area of metabolic
pathways and fate of chemicals found to be carcinogens in animals.
Efforts to develop rapid assays for mutagenesis and carcinogenesis
have recently been greatly expanded. Methods that show promise include
tests for mutagenicity that make use of bacterial, cell transformation, and
organ culture systems. There appears to be high positive correlation
between mutagenicity, as determined by some of these methods, and
carcinogenicity in agents already studied (McCann et al., 1975; McCann
and Ames, 1976; Ames, 1976~. The utility of these rapid methods will
depend on experimental demonstration that their results are well
correlated with those obtained from conventional long-term studies of
carcinogenicity with well-designed animal systems. High priority should
be given this research because it offers a reasonable probability of success
in a relatively short time and at lower cost than long-term testing, and
there is an urgent need for a primary screen for selecting compounds for
long-term assay (DHEW, 19771.
The committee is fully conscious of these modern methods for
determining genetic and physiological phenomena. Their use, when
appropriate, and their further development is strongly encouraged.
Pollutants in water have many different effects. At- one extreme, they
can impart a disagreeable taste or odor. This is quickly perceived by the
community, and the process of characterization and identification of the
offending pollutant is generally prompt and fairly straightforward. At the
other extreme, the ejects on human health of a carcinogen present in
drinking water will probably go undetected, particularly if it produces
only a modest in-crease in the incidence of a common cancer.
The major toxicological and epidemiological efforts should therefore
be directed to characterizing and identifying pollutants whose biological
effects include chronic, irreversible, and progressive diseases, such as
cancer. It is necessary to develop risk estimates for large human
populations of varied susceptibilities that are exposed to small concentra-
tions of such toxic pollutants, including carcinogens.
The development of safety factors for pollutants whose toxic ejects are
reversible and nonprogressive involves empirical calculations based on
past history of use and concentrations that appeared safe for the public.
These safety factors are usually applied to the highest dose or concentra-
tion at which no adverse eject was observed. The chosen dose or
concentration is divided by a "safety factor" that varies over a wide
range, depending on the adequacy of the data.
Whether or not the "safety factor" approach can be used with
pollutants that cause chronic, irreversible, and progressive disease in
laboratory animals is controversial. Those who argue for safety factors,
OCR for page 21
Chemical Contaminants: Safety And Risk Assessment 21
and thereby thresholds, find it inconceivable that very small concentra-
tions can cause a cancer to develop, claiming that body defenses can
surely protect at doses smaller than the threshold value. Those who argue
that safety factors are inadequate and that almost no thresholds can be
determined, or theoretically developed, suggest that even one or a very
few molecular events have a finite probability of initiating a successful
malignant or neoplastic transformation in a cell, and that this can lead to
a lethal cancer. Although one malignant cell can lead to death by cancer,
many liver or kidney cells can be killed or damaged (but not malignantly
transformed), without causing any detectable disease. Furthermore, man
is never exposed to one carcinogen at a time, but is exposed to low
concentrations of many at the same time.
Accordingly, we have adopted a "nonthreshold" approach for estimat-
ing risks from pollutants that have been shown to be carcinogenic in
laboratory animals.
Demonstration that a pollutant is carcinogenic, and application of
nonthreshold risk estimates to it, do not imply that its use must be
prohibited. Such a proscription might itself give rise to even greater risks
to health or other disadvantages. In some cases, a net risk must be
estimated, and society must attempt to use the pollutant in such a way as
to minimize risk and maximize benefit. Nowhere is this better illustrated
than in the use of chlorination to disinfect water. Chlorination controls
pathogenic organisms, but introduces chloroform, which is carcinogenic
in animal-test systems. Methods must be devised to minimize concentra-
tions of chloroform and chlorinated hydrocarbons, from whatever
source, in drinking water. But before alternative methods for control of
pathogenic organisms are instituted, toxicological studies must show that
they are as effective as, and pose no greater risk than, chlorination. We
perceive that society is willing to accept some risks to health if the
attendant benefits are demonstrably greater.
Drinking water contains low concentrations of many chemicals, some
of which, if ingested for a long time, could have delayed toxic effects. The
insidious eject of chronic exposure to low doses of toxic agents is difficult
to recognize, because often there are few early warning signs and, when
signs are ultimately observed, the effects may have become irreversible.
Subchronic toxicology studies may not offer reliable means for assess-
ment of long-term toxic effects in animals, let alone extrapolation to
chronic effects in man; hence, different considerations have to be applied
in assessing risk. The methods and principles of acute toxicology do not
offer any easy, straightforward methods for extrapolation of such
experimental data to calculate risks for large human populations.
Two important questions must be answered: What assay procedures
.. .
OCR for page 22
22 DRINKING WATER AND H"LTH
are required for a valid assessment of chronic toxicity of chemicals in
experimental animals? How can the data from such procedures be
extrapolated to estimate risks in humans? In dealing with these questions,
we use the specific risk of cancer as our major example, although other
toxicities are considered. This report seeks to summarize the state of the
art in extrapolating to man the results of experiments on animals, chiefly
in relation to carcinogenesis.
EFFECTS ON HEALTH
The purpose of drinking-water standards is to ensure protection from
acute poisoning and from long-term, or "chronic," effects. In recent
years, numerous short-duration, presumptive tests in vitro have been
developed that may help to predict carcinogenesis. Nonetheless, studies
of chronic toxicity continue to be required for safety evaluations. These
are necessary because there is no general way to predict carcinogenic
elects on the basis of the observed short-term elects of chemical-
biological interactions. [The significance to health of the finding that a
pollutant is mutagenic in the new test systems is unknown (See Drake,
1975; DHEW, 1977~. But, because evidence of the correlation between
mutagenicity and carcinogenicity continues to accumulate, we suggest
that a conservative safety factor be provisionally applied to the
mutagenicity data and that, if new information (such as the results of a
reliable carcinogenicity study) is lacking 4 yr from the time a mutagenici-
ty study is completed, nonthreshold methods be used to establish risk.]
Chronic exposures and chronic effects are different (Casarett, 1975~.
The former means frequent ingestion over a long period of time. The
latter implies injury that persists, either because the injury is irreversible
or progressive, or because the exposure is prolonged and the rate of new
injury exceeds the rate of repair. Chronic exposure in animals is generally
considered to be at least half the life span. In man, it can be much less.
Injury from chronic exposure may occur in at least three ways: by
accumulation of the chemical to a critical concentration at sites of action
sufficient to induce detectable injury;
by accumulation of injury until
physiological reserves can no longer compensate (i.e., repair is never
complete); or after a long, latent period beginning with an exposure that
has an unrecognized biological elect, and precipitates the eventual
appearance of injury. In the first case, knowledge of the kinetics of
chemical absorption, metabolism, and excretion obtained in short-term
studies may allow computation of the amount of the toxic chemical that
will accumulate in long-term use. Such investigations will improve the
OCR for page 23
Chemical Contaminants: Safety And Risk Assessment 23
usefulness of long-term, low-dose, chronic-exposure studies. To predict
chronic accumulation, or latent development, of injury from the results of
short-term tests requires knowledge of the kinetics of injury and repair.
There are few, if any, substances for which such understanding is at hand.
Reversibility of Chemical Injury
Reversible elects disappear after exposure ends. The time required for
return to normal should be a small fraction of the remaining lifetime of
an organism. During the period of return to normal, the organism must
be at no greater risk (than one that was never exposed) of further or other
damage from other sources. For some elects, reversibility may be
qualified by the normal lifetime of a specific cell or macromolecule that
serves as the end point of the elect. A nonreversible effect is one in which
the damage does not regress completely, or may progress after exposure
ceases.
Some erects of toxic chemicals are unmistakably irreversible. They
include terata, malignant tumors, mutations in offspring of exposed
animals, and some neurological changes. These are gross manifestations
of specific chemical-cell interactions, and it is possible, or probable, that
there are early reversible effects, either in the cellular process first affected
or at intervening stages. Prediction of adverse effects from short-term
studies is possible if the critical dose and the rate-limiting factors that
determine reversibility are known. Without this knowledge, evaluation of
toxicity will generally deal more with the possibility of irreversible effects
than with speculatively reversible elects.
Net reversibility varies from one tissue, species, strain, or individual to
another. It is generally impossible to measure the specific processes
involved in injury and repair in the standard toxicity-evaluation study.
However, measurements of reversibility in short-term studies should
provide useful information that may allow extrapolation to the longer
term.
The predictive value of such tests does not necessarily depend on the
persistence of the chemical in the test organism. If the chemical produces
a reversible erect and then is rapidly detoxified or excreted, it may be
possible to compute the doses or schedules of exposure that would not
produce cumulative and ultimately nonreversible or irreversible effects
(see definitions below). But other factors might be overriding. For
example, rapid reversibility after a single dose might not indicate the rate
of reversal after repeated doses, if the first dose, in addition to the
measured erect, altered the repair process or processes responsible for
detoxification (Murphy, 1967~. To evaluate repeated-dose effects, sub
OCR for page 24
24 DRINKING WATER AND H"LTH
chronic- and chronic-exposure studies should include groups of animals
that are removed from exposure at selected intervals during the
experiment. The rate of reversal of elects in these animals can be
measured at intervals, or at some critical time after exposure ceases.
If the chemical persists in the organism, quantification of rates of
reversal is more complicated. Data are needed on absorption and
disposition to correspond with data on rates and reversal of elects.
Perspectives and Perceptions of Effects
Whether an elect is reversible, nonreversible, or irreversible might be
shown by experiments (or epidemiological studies) that include observa-
tions during exposure-free "recovery"periods similar to those made at the
end of the exposure period. Nonreversible and irreversible injuries are of
greater concern than reversible injuries in evaluating human health
elects. However, frequently recurring reversible injury may lead to
greater morbidity than a nonreversible or irreversible injury that appears
only late in life. Characterization of an effect as reversible implies that
there is a dose below which health will not be compromised. This
assumes, of course, that any subliminal cellular injury that is responsible
for the manifest elect is also reversible. Full understanding of thresholds,
margins of safety or safety factors, and extrapolations of estimated risk
requires understanding the underlying cellular mechanisms of injury.
An alternative to the safety-factor approach for reversible toxicity may
be considered. The nonthreshold approach is attractive partly because of
the idea that one transformed cell could lead to fatal neoplastic disease.
What number of damaged (but not transformed) or killed kidney, liver,
or lung cells is compatible with a healthy life? If these numbers, or
fractions of total organs, could be estimated for a number of species,
including man, and if experimental dose-response curves for fractional
damage to all vital organs could be obtained, the numbers of damaged
cells that are compatible with health could be estimated. This might
constitute an initial approach to the development of rational risk
estimates for toxic effects other than cancer. Clearly, a major research
effort is needed.
Where it was once common to refer to "no-effect doses" of chemicals
and "safe" doses, it is now more appropriate to speak of"no-observed-
adverse-e~ect" doses and "acceptable risk" when describing permissible
use or exposure to chemicals. This change has been accompanied by an
increasing concern for the health of the most susceptible individuals in
OCR for page 25
Chemical Contaminants: Safety And Risk Assessment 25
the population, besides that of the average individual. Many scientists
now distinguish between injuries produced by chemicals for which there
is likely to be a threshold dose and elects (e.g., carcinogenesis and
mutagenesis) for which there is likely to be either no threshold dose or no
way presently known to estimate one for large, heterogeneous popula-
tions. [A report of another committee of the National Academy of
Sciences expresses some doubt about the validity of the threshold concept
for any type of biological erect (NAS, 1975~; see also Drake et al., 1975,
and Hoel et al., 1975.] From another point of view, Well (1972),
considering statistics and judgment in safety evaluation, wrote: "No
matter what the biological erect, at some concentrations under some sets
of conditions, a dose level must exist below which no biological damage
will occur during the life-span of the great majority of men. No matter
how small the dose, however, one, or a few, of millions of subjects may
exhibit the critical response."
It is more prudent to treat some kinds of toxic elects that may be self-
propagating or strictly cumulative, or both, as if there were no threshold
and to estimate the upper limits of risk for any given exposure. Included
among these are elects that result from an initial, chemically induced
alteration in cellular genetics that is transmitted by cell propagation.
Carcinogenesis and mutagenesis are examples in which a single cell
transformation has the theoretical potential for irreversibility, which
might involve self-propagation, even in the absence of further exposure.
Other injuries may become self-propagating-e.g., advanced stages of
cirrhosis but they are usually preceded by detectable injury that is
reversible. The initial erects should have a dose-response threshold,
inasmuch as the nature of cellular injury that precedes them can be
detected while the injury is still reversible.
Some forms of injury may be strictly cumulative, because the cells in
which they occur are not repaired or replaced. (For example, destruction
of enough neurons leads to a decrease in central nervous system
function.)
Congenital malformations appear to be irreversible. In this case, injury
occurs from exposure during only a brief period. In addition, it is
probable that a threshold dose could be estimated from adequate
experimental or epidemiological data.
Current knowledge of the proper principles for extrapolating toxicolog-
ical data from high dose to low dose, and from one species to another, is
inadequate. Nonetheless, standards for drinking water must be devel-
oped. Whenever possible, a maximal no-observed-adverse-effect dosage
should be identified. Three major categories of erects should be
OCR for page 26
26 DRINKING WATER AND H"LTH
considered, and different ways of arriving at standards can be proposed
for each.
Irreversible (SeIf-Propagating) Effects
(These are likely to become life-threatening even after exposure has
ceased)
1. Genetically self-propagating ejects, e.g., somatic or germ-cell
mutation that culminates in a malignant neoplasm or is transmitted to
later generations: Assume no threshold, assume a linear dose-response at
low doses, and estimate risk. Set standard at something other than zero
only if exposure cannot be eliminated by reasonable means, or if material
has no safer substitute, and if it has great utility or social value. An
acceptable degree of risk arrived at by a case-by-case consideration
involving numerous scientific, technological, economic, and societal
issues and values should determine the permitted dose.
Nonreversible Effects
1. Ejects that are sequels to probably detectable, reversible injury, but
that may become self-propagating (such as cirrhosis): If a threshold can
be demonstrated, use it as an upper limit, with application of an
appropriate safety factor. If not, proceed as in "Irreversible Ejects."
2. Death of irreplacable cells, cumulative with continued exposure,
e.g., central nervous system disease, as in exposure to methyl mercury. If
a threshold can be demonstrated, use it as an upper limit, with
application of an appropriate safety factor. If not, proceed as in
"Irreversible Effects."
Reversible Effects
1. Life-threatening or major morbidity, e.g., inhibition of a vital
enzyme system. If a threshold can be demonstrated, use it as an upper
limit. If not, proceed as in "Irreversible Ejects."
2. Minor morbidity, e.g., sensory irritation without histological
change. Determine the range of sensitivities and choose an upper limit
low enough to minimize occurrence in the population.
3. No detectable functional or sensory decrement, but possibly
predictive precursor of more serious effect, e.g., plasma cholinesterase
inhibition, or small increase in liver enzymes in plasma. Proceed as in 2.
OCR for page 27
Chemical Contaminants: Safety And Risk Assessment 27
IRREVERSIBLE TOXICITY
Many factors make the assessment of long-term health risks to human
populations difficult for example:
1. The sensitivity of the test systems used to detect carcinogenic ejects
depends on the number of animals used in each test and on the duration
of their survival.
2. Any series of experiments will yield false-positive and false-negative
results.
3. Detection of neoplastic changes in treated animals requires exten-
sive gross and microscopic examination of many tissues by trained
people.
4. Time, resources, and money required to conduct an adequate test
are all substantial.
Controversies have arisen because of the above problems and because
of inadequate testing for long-term effects. False-positive results can
cause unnecessary public concern and the removal of useful materials
from the market, and false-negative results can endanger the health of
large groups of people. Long-term ejects are particularly difficult to
detect and treat because they are discovered only after many years, by
which time they are often irreversible.
The main question to be answered is: "Within the limitations of
present-day capabilities, what are the minimal requirements for an
adequate test (on experimental animals) of the long-term effects of
potentially toxic agents, and how can these results be used to estimate
possible risk to the human population?"
Summary of Principles for Extrapolating Animal Toxicity To
Humans
Despite wide gaps in our knowledge of the metabolism and ultimate fate
of chemicals in man, properly conducted experiments will yield results
that can improve our estimates of the risk to human populations from
long-term exposures.
Many mechanisms for chemical carcinogenesis have been postulated.
If the mechanism involves somatic mutation or alteration, there is no
threshold dose for long-term exposure; if the mechanism is unknown, it is
prudent to assume that DNA damage is involved. The idea that there is a
"safe" dose of such chemicals may be conceptually valid, but "safety"
cannot be established by any experimental method now available. Every dose
OCR for page 28
28 DRINKING WATER AND H"LTH
should be regarded- as carrying some risk. A "most probable risk" can be
estimated by appropriate statistical treatment of the results of experi-
ments on animals, and once the benefits of use of a chemical have been
defined and estimated, it is possible to weigh the health risks against the
health benefits. The balance between them should then be the overriding
consideration in regulating the amounts of such substances in the
environment.
The method used in classical toxicology for determining safe doses for
short-term exposure of humans to drugs is to estimate a maximum
exposure that is tolerated without adverse ejects in a group of animals,
and to apply a safety factor. This procedure is valid only for estimating
the risk of reversible toxic effects. "No-observed-adverse-effect dose" is a
better term, because it makes clear that the exposure can often be a
function of the size of the experiment the larger the experiment, the
lower this dose can be.
Studies in laboratory animals must be used to predict the safety of
environmental chemicals. Human epidemiological studies cannot be used
to predict nor assure safety, for several reasons:
1. Epidemiology cannot tell what effects a material will have until after
humans have been exposed. One must not conduct what might be
hazardous experiments on man.
2. If exposure has been ubiquitous, it may be impossible to assess the
ejects of a material, because there is no unexposed control group.
Statistics of morbidity obtained before use of a new material can
sometimes be useful, but when latent periods are variable and times of
introduction and removal of materials overlap, historical data on chronic
ejects are usually unsatisfactory.
3. It is usually difficult to determine doses in human exposures.
4. Usually, it is hard to identify small changes in common ejects,
which may nonetheless be important if the population is large.
5. Interactions in a "nature-designed" experiment usually cannot be
controlled.
With the possible exception of arsenic and benzene, the known human
carcinogens are carcinogenic in some laboratory species. Therefore,
animal studies of carcinogenesis in laboratory animals are useful for
predicting effects in man.
Thus, for ethical and practical reasons, data derived by using animals
for toxicity testing are essential for protecting the public from harmful
effects of new chemicals in the environment and probably also necessary
for evaluating the potential harm of "old" chemicals. By the same token,
OCR for page 29
Chemical Contaminants: Safety And Risk Assessment 29
epidemiological surveillance studies are necessary for detecting the errors
that will surely arise from use of the animal studies alone. Thus,
epidemiological studies are both a last line of defense and a means for
verifying and adjusting the conclusions from animal studies.
The General Problem Of Extrapolation
The knowledge and insight that provide a basis for more successful
extrapolation are rapidly increasing. The value of tests on laboratory
animals is most easily estimated when the chemical agents tested are
ultimately administered to, or confront man in a manner similar to the
animal exposure, as in the drug-development process. The sequence of
animal tests of a new chemical agent, after toxicological studies,
continues with studies conducted in order to determine: the mechanism
through which the laboratory animals respond to the agent, the nature of
its metabolism in tissues and organs, and the rates and routes of
elimination of the agent and its derivatives. Thus, damage observed in an
organ of an animal provides clues that lead to an understanding of the
metabolism and organ involvement of the substance in humans.
Similarities and differences between humans and animals can be noted,
and the validity of the laboratory-animal test systems can be better
estimated. This approach is most useful for observing early elects that
occur soon after the substance is administered. The use of such data for
assessing long-term effects in humans has many difficulties.
When a mouse or man is exposed to a chemical, a number of events
can occur that can greatly influence the final reaction, which may appear
as the observed toxic elect. These events include: absorption; distribu-
tion and storage; metabolism, excretion, and reabsorption; arrival at the
site of action; reaction with the biological receptor; and interaction with
other constituents of the environment. They can be compared among
various animal species and among strains and individuals. Anatomical,
biochemical, physiological, pharmacological, and pathological differ-
ences and similarities can and have been identified, and there have been
efforts to characterize systematically the differences and similarities
between species for some compounds and classes of compounds. These
are appropriate subjects for research.
Chemicals to which man is exposed can be divided into two classes:
those deliberately administered for therapeutic, diagnostic, or nutritive
purposes, which contribute to health, and those with uses that do not
directly benefit health, but reach man through a variety of routes.
To some extent, the acute toxicity of the first class can be observed
directly in man. If the chemicals are already in use, the laboratory-animal
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52 DRINKING WATER AND H"LTH
background." This kind of interaction phenomenon has important
implications for the models used in extrapolation. It implies that these
models may not assume any threshold for a new material in a world
already populated by many carcinogens. It also leads to the conclusion
by Crump et al. (1976) that "all models of carcinogenesis thus far
proposed will be linear at low doses."
The discovery of interactions will require more sophisticated experi-
mental techniques than are now being used. Testing combinations of
materials multiplies the number of tests that must be done (100 materials,
tested two at a time, will require 100X 99/2! tests; tested three at a time
will require 100 x 99 x 98/3! tests). New techniques for multiple testing
will have to be developed. Uncovering deficiency interactions will require
entirely new and different approaches.
SUMMARY Chemical Contaminants: Safety and Risk Assessment
Large populations are repeatedly exposed to potentially toxic contami-
nants in the drinking water in minute amounts over many months or
years, or over whole lifetimes. Delayed, essentially irreversible, ejects can
occur. Methods and criteria of classical, conventional toxicology do not
offer reliable means for assessing long-term toxic ejects such as
carcinogenesis in man by extrapolation from animal data; hence, novel
considerations have to be applied in assessing risk.
The insidious ejects of chronic exposure to low doses of toxic agents is
difficult to recognize, because there are few, if any, early warning signs
and, when signs are ultimately observed, they often imply irreversible
ejects. For example, cancer induction in experimental animals, even with
the most potent carcinogenic chemicals, requires at least several months
and in many instances a whole lifetime. There are as yet no easy,
straightforward methods for extrapolating even chronic-exposure experi-
~nental data to calculate risks to large human populations. Teratogenic
ejects are easier to establish by animal experimentation, but there are
similar uncertainties in extrapolating to human populations. Mutagenic
ejects are difficult to assess experimentally in mammals, and such ejects
are particularly insidious, in that they appear only in later generations.
Various measures used in assessing acute toxicity such as LD~o,
LD50, and maximal tolerated dose are generally found to be quantita-
tively similar among most animals. On the basis of dose-per-unit of body
surface, toxic ejects in man are in the same range as those in
experimental animals, such as mouse, rat, hamster, dog, and monkey. On
a body-weight basis, man is generally more vulnerable than the
OCR for page 53
Chemical Contaminants: Safety And Risk Assessment 53
experimental animal, probably by a factor of ~12. Comparative studies
have shown generally that absorption, metabolism, and excretion of
various drugs are slower, dose-for-dose, in man; that there is greater
retention of such drugs; and that higher concentrations occur in body
fluids and tissues in man than in small mammals. With an awareness of
these quantitative differences, appropriate safety factors can be applied to
calculate relatively safe therapeutic dosages for man. These methods and
principles of classical toxicology are useful for assessing toxic effects that
are reversible and nonprogressive. They are much less useful in dealing
with the problems of chronic irreversible toxicity or the effects of long-
term exposure. This subject has not been considered widely in the past.
From the review of available information, two major questions emerge:
"What types of experimental-assay procedures are required for a valid
assessment of chronic toxicity of chemicals in experimental animals?"
"How can such data be extrapolated to estimate risks in humans?" In
dealing with these questions, our recommendations are restricted to a
specific risk namely, cancer with the understanding that the same
considerations will apply at least partially to the problems of mutagenesis
and teratogenesis. Furthermore, we consider only carcinogens whose
mechanisms involve somatic mutations.
Some principles that underlie efforts to assess the irreversible effects of
long-continued exposure to carcinogenic substances at low dose rates are
outlined below.
Principle 1
EFFECTS IN WAS, PROPERLY QUALIFIED, ~ ITALIC - LE TO ~
This premise underlies all of experimental biology and medicine, but
because it is continually questioned with regard to human cancer, it is
desirable to point out that cancer in men and animals is strikingly similar.
Virtually every form of human cancer has an experimental counterpart,
and every form of multicellular organism is subject to cancer, including
insects, fish, and plants. Although there are differences in susceptibility
between different animal species, between different strains of the same
species, and between individuals of the same strain, carcinogenic
chemicals will affect most test species; and there are large bodies of
experimental data that indicate that exposures that are carcinogenic to
animals are likely to be carcinogenic to man, and vice versa.
Evidence that circumstances leading to cancer induction in humans are
also applicable to experimental animals stems from the very first
observation of chemical carcinogenesis the appearance of cancer of the
OCR for page 54
54 DRINKING WATER AND H"LTH
scrotum in chimney sweeps, observed by the British surgeon, Percival
Pott, in 1775. It was not until modern times that a substance implicated in
human cancer was found to be carcinogenic in animals, when the
Japanese scientists, K. Yamagiwa and K. Ichikawa, found in l91S that
extracts from coal tar cause cancer when applied to the skin of
experimental animals. Many pure carcinogenic chemicals have since
been isolated from a wide variety of"tars" derived from incomplete
combustion of organic matter, such as coal, wood, and tobacco. There is
little doubt that these and other chemicals, alone or in combination, are
responsible for the greatly increased incidence of lung cancer among
smokers. With the possible exception of arsenic and benzene, all known
carcinogens in man are also carcinogenic in some species, although not in
all that have been tested.
Principle 2
METHODS DO NOT NOW EXIST TO ESTABLISH A THRESHOLD FOR LONG
TERM EFFECTS OF TOXIC AGENTS
With respect to carcinogenesis, it seems plausible at first thought, and it
has often been argued, that a threshold must exist below which even the
most toxic substance would be harmless. Unfortunately, a threshold
cannot be established experimentally that is applicable to a total
population. A time-honored practice of classical toxicology is the
establishment of maximal tolerated (no-e~ect) doses in humans based on
finding a no-observed-adverse-e~ect dose in chronic experiments in
animals, and to divide this dose by a "safety factor" of, say, 100, to
designate a "safe" dose in humans. There is no scientific basis for such
estimations of safe doses in connection with carcinogenesis. For example,
even if no tumors are obtained in an assay of 100 animals, this means only
that at a 95% confidence level, the true incidence of cancer in this group
of animals is less than 3%. Even if we were to carry out the formidable
task of using 1,000 animals for assay and no tumors appeared, we could
only be 95% sure that the true incidence were less than 0~3%. Obviously,
0.3% is a very high risk for a large human population.
In fact, there are no valid reasons to assume that false-negative results
of carcinogenicity tests are much less frequent than false-positive ones.
To dismiss all compounds that did not induce tumors in one or two
mouse and rat experiments as noncarcinogenic is wrong. Labeling as
"carcinogens" all substances that gave rise to increased incidence of
tumors is justified only if there is conclusive evidence of a causal
relationship. The "relative risk" of compounds that are not found to
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Chemical Contaminants: Safety And Risk Assessment 55
induce tumors in animal experiments must also be considered. But this
requires evaluation of data other than those collected in chronic toxicity
studies on rodents.
Experimental procedures of bioassay in which even relatively large
numbers of animals are used are likely to detect only strong carcinogens.
Even when negative results are obtained in such bioassays, it is not
certain that the agent tested is unequivocally safe for man. Therefore, we
must accept and use possibly fallible measures of estimating hazard to
man. This reasoning leads us to the statement of Principles 3 and 4.
Principle 3
THE EXPOSURE OF EXPERIMENTAL ANIMALS TO TOXIC AGENTS IN HIGH
DOSES IS A NECESSARY AND VALID METHOD OF DISCOVERING POSSIBLE
CARCINOGENIC HAZARDS IN MAN
The most commonly expressed objection to regulatory decisions based on
carcinogenesis observed in animal experiments is that the high dosages to
which animals are exposed have no relevance in assessment of human
risks. It is therefore important to clarify this crucial issue. Practical
considerations in the design of experimental model systems require that
the number of animals used in experiments on long-term exposure to
toxic materials will always be small, compared with the size of the human
populations similarly at risk. To obtain statistically valid results from
such small groups of animals requires the use of relatively large doses so
that effects will occur frequently enough to be detected. For example, an
incidence as low as 0.01% would represent 20,000 people in a total
population of 200 million and would be considered unacceptably high,
even if benefits were sizable. To detect such a low incidence in
experimental animals directly would require hundreds of thousands of
animals. For this reason, we have no choice but to give large doses to
relatively small experimental groups and then to use biologically
reasonable models in extrapolating the results to estimate risk at low
doses. Several methods of making such calculations have been considered
and used, but we think that the best method available to us today is to
assume that there is no threshold, and that the incidence of tumors is
directly proportional to dose. However, it is important to recognize that
such calculations may give either too small or too large an estimate risk.
The actual risk to humans might be even greater over a human lifetime,
because it is about 35 times that of a mouse; and there is evidence that the
risk of cancer increases rapidly with the length of exposure. Moreover,
experimental assays are conducted under controlled dietary and environ
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56 DRINKING WATER AND H"LTH
mental conditions with genetically homogeneous animals, whereas
humans live under diverse conditions, are genetically heterogeneous, and
are likely to include subpopulations of unusual susceptibility.
It should be emphasized that these general considerations give only a
minimal estimate of human risk; moreover, they do not take into
consideration differences in susceptibility between species. For example,
beta-naphthylam~ne is well established as a human carcinogen on the
basis of epidemiologic studies of occupationally exposed workers,
whereas experiments have not shown it to be carcinogenic in the hamster,
which is relatively resistant.
Not all substances that cause a given incidence of cancer in the rat are
equally carcinogenic for man. This means that chronic-toxicity studies,
which are imperfect assay systems for carcinogenicity testing, should not
be used as the sole criterion in the assessment of risk.
Principle 4
MATERIAL SHOULD BE ASSESSED IN TERMS OF HUMAN RISK, RATHER
THAN AS SAFE OR UNSAFE
The limitations of the current experimental techniques do not allow us to
establish safe doses, but with the help of statistical methods we may be
able to estimate an upper limit of the risk to human populations. To
calculate such a risk, we need data to estimate population exposure; a
valid, accurate, precise, and reproducible assay procedure in animals;
and appropriate statistical methods. Several general guidelines may be
presented. First, no rigid, generally applicable procedure can be
recommended for testing all toxic agents. Substances diner too much in
their overall effects, and the design of appropriate assays will ultimately
have to be left to the well-informed judgment of expert investigators. If
substances that affect large populations are found to be carcinogenic,
experiments of much wider scope may have to be conducted to obtain
more detailed information on their possible ejects in humans. As a
pragmatic guideline, it would be desirable to test a compound for
carcinogenicity in at least two species, such as the mouse and the rat, and
the strains of animals used should have a rather low incidence of
spontaneous tumors under the conditions of the test. It is important to
include "positive" controls, with known carcinogens, under the same
conditions used for the test animals. This has been a point of considerable
controversy.
Experiments should be conducted over as much of the lifetime of the
experimental animal as possible. The highest dose should be the
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Chemical Contaminants: Safety And Risk Assessment 57
maximum that is tolerated without shortening the lifespan through causes
Other than cancer. Every animal, whether it dies during the exposure
period or is sacrificed at the end of the experiment, should be examined
grossly and microscopically, and all toxic effects (not only cancer) should
be noted.
Risk constitutes but half the essential comparison that should be made
in the assessments of human hazard; the other half is benefit to the
exposed population of the agent for which hazard has been identified.
Decisions cannot involve merely the risk. Statements of benefits should
include the nature, extent, and recipient of the benefit. Technology has
always been associated with some risk. But the acceptability of risk
should depend on the specific benefits derived, the nature of the
population exposed, and the availability of practical alternatives.
It is not possible to guarantee a risk-free society; nor is a risk-free
society necessarily the best society. It is often necessary to accept the risks
of chemicals such as drugs and pesticides when the benefits warrant
their use. Risks imposed on persons who gain no benefits are generally
not acceptable. Personal choice and personal values enter into the risk-
benefit comparison. For major benefits- for example, in the treatment of
otherwise incurable or incapacitating diseases much higher risks are
allowable than otherwise. An important principle in risk-benefit assess-
ment is that each person must be allowed the widest possible choice
supported by full information on risks, as well as benefits so that
intelligent choices may be made.
The benefit portion of the equation should be well defined by
knowledgeable experts, and based on data at least as good as the risk
data. It is important, therefore, that the benefit-risk comparisons be
established with the active cooperation of people who are qualified to
assess the usefulness of a substance and the consequences to those in
need of it, as well as to the population at large.
Finally, mankind is already exposed to many carcinogens whose
presence in the environment cannot be easily controlled. In view of the
nature of cancer, the long latent period of its development, and the
irreversibility of chemical carcinogenesis, it would be highly improper to
expose the general population to an increased risk if the benefits were
small, questionable, or restricted to limited segments of the population.
Principles To Be Used for Noncarcinogens and Nonmutagens
The nature and reversibility of the toxic eject must be considered.
For carcinogens that are not shown to be mutagens, some sort of
extrapolation must be postulated.
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58 DRINKING WATER AND H"LTH
For noncarcinogens for which it seems likely that there are thresholds
for toxic ejects, the acceptable dose should be below the threshold. If a
threshold cannot be shown, the acceptable dose must be related to the
data from animal experimentation and consideration of the seriousness of
the toxic effects, as well as the likelihood and ease of reversibility, the
variability of the sensitivity of the exposed population, and the economic
and health-related importance of the material.
RESEARCH RECOMMENDATIONS
Research must be supported to develop an understanding of the
mechanisms by which water pollutants produce toxic effects. This
includes pharmacokinetics, tox~cation-detoxication mechanisms, and
biochemical and pathological mechanisms of action.
Estimates of margin of safety can be made more precisely and
rationally as more is known about what happens to a chemical in the
body and what the chemical or its metabolites do to the body. The results
of such research also are necessary to develop rapid, inexpensive,
accurate screening tests for various critical forms of toxicity.
It is recognized that much of this research is going on, but the
Committee is convinced that more must be done. In protecting the
population of the United States from environmental pollution there is no
more important or potentially- productive effort than the support of this
kind of research. Since these studies are long-term in nature and must be
closely coupled to basic biomedical research, they should be supported
primarily by research rather than regulatory agencies.
There are many research needs in the field of chronic disease
epidemiology. Manpower is in critically short supply. There are critical
problems of data resources.
Research on statistical methods and mathematical models for estimat-
ing low dose ejects should be encouraged. Statistical work is pratically
nonexistent for effects other than carcinogenesis. Although a consider-
able effort has been expended on dose-response estimation for carcino-
genesis, very little has been done on species variability and susceptible
subgroups. This area could at least be studied from an empirical
standpoint so that there would be a better understanding of the precision
of low-dose risk estimates.
These recommendations are summarized below:
1. Studies of the physiological and biochemical mechanisms by which
the toxic substances in water produce their ejects.
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Chemical Contaminants: Safety And Risk Assessment 59
2. Development of rapid, inexpensive, and precise tests to identify
substances that may produce important toxic ejects at low doses and
dose rates.
3. Epidemiological studies of chronic disease.
4. Research on statistical methods and analytical models for describ
ing and estimating the ejects of long exposure to low doses of toxic
substances. Studies should not be limited to carcinogenesis and should
consider, also, differences between species, and particularly sensitive
subgroups in the population.
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Representative terms from entire chapter:
low doses
