Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 100
CHAPTER 5
APPLICATION OF THE
MODEL TO CHEMICAL HAZARDS
The Committee on the Scientific Basis of the Nation's Meat and
Poultry Inspection Program (NRC, 1985 ~ described the various sources of
chemical residues in meat and poultry products and the approach used by
FSIS to control them. That committee also made several recommendations
for improving the FSIS inspection program and urged the adoption of
formal risk-assessment procedures to provide maximum protection of
public health. Specifically, the committee recommended that risk
assessment play a major role in the establishment of limits for
chemical residues in meat and poultry products destined for human
consumption, in the prevention and characterization of hazards, in the
setting of priorities for controlling residues, and in the design of
sampling methods. This chapter contains a discussion of risk assess-
ment as a guide to the management of chemical hazards in poultry
products, criteria for j udging the safety of poultry products con ~
tanning residues, some approaches to ensuring that safety criteria are
met, and the types of data and analysis needed to assess the public
health impact of chemical residues in poultry products. It also
identifies the necessary elements of a risk-management program and
describes the risk-assessment methods needed to establish this
program . It does not include cons iteration of current FSIS inspection
which is evaluated in subsequent chapters of the report.
&; ~
GENERAL METHODS FOR ASSESSING THE PUBLIC HEALTH RISKS OF CHEMICALS
There is extensive documentation on deaths and injuries from
accidental poisonings by household products, pesticides, and thera-
peutic agents. Ordinarily there is little difficulty in estimating the
relationship between the extent to which these substances are used and
the frequency of poisonings and in documenting the association between
a given exposure and a given poisoning when the effect is immediately
observable (i.e., acute). It is more difficult to assess risks
associated with chemical exposures when no immediately observable
effects are produced when the fact or degree of exposure is itself
highly uncertain. Since most chemical exposures associated with
residues in poultry products are uncertain, the risks must be predicted
and those predictions used to set health protection standards.
100
OCR for page 101
101
Although the methods used to predict chemical risks are uncertain
(e.g., because of incomplete data, the need to extrapolate beyond data,
and the lack of knowledge concerning the extent of future human
exposure), they are based on a strong scientific foundation (NRC,
1980b, 1983~. The safe use of products, including food ingredients,
pesticides, and drugs, depends upon these methods of risk prediction
and their use in the establishment of low risk (or safe) exposures
(FSC, 1980~.
People are exposed to a large number of naturally occurring and
man-made chemicals through poultry products and other environmental
media. If they are to be protected from the possible adverse effects
of these substances, methods to assess the risk assessment of such
exposures must be applied. It is a premise of this report that
predictive methods developed for and widely used in many areas of
public health protection are appropriate for assessing the risks of
exposure to chemical residues, establishing appropriate health
protection standards for such residues, and guiding the development of
programs to manage the risks presented by the residues. Parts or all
of the s premise have been adopted by the Food and Drug Administration,
the Environmental Protection Agency, and other government agencies
charged with protecting consumers from such residues, especially for
risk assessment and the establishment of standards. However, there are
important limitations in the methods themselves and in their
application to specific problems, including those associated with
poultry products.
THE COMPONENTS OF RISK ASSESSMENT
A National Research Council committee described four basic
components of risk assessment in the federal government: hazard
identification, dose-response assessment, exposure assesment, and risk
characterization (NRC, 1983~. Figure 5-1 shows the relationships
between these components of risk assessment, research, and risk
management.
Hazard Identification
Toxicity. All chemical substances, whether natural or man-made,
can cause some form of biological injury under some conditions of
exposure. The purpose of the first phase of risk assessment is to
collect and evaluate information on the inherent toxic properties of
chemicals of interest. Identifying these properties is not equivalent
to identifying possible risk. Thus, it should not be assumed that a
substance displaying toxicity presents a risk to human health. All
steps of risk assessment must be completed before any statement can be
made about risk.
OCR for page 102
102
0
o So
o °
E ~
~ o
_ It
he
5
In
In
U)
In
In
fir:
0
Ca,
3 _
O ~ Co
3 0=
~ =0
CON
~ 0 ~
S ~ 5:
I
G
CO
2 E ° en
Al C AL C O
~ 0 ° a, 2
-
° ~E ~ ~
~ 0— ~ _
,,, = ~ ~ O
~ ~ ~ 0 ~
,1
0
0
~ 0
0
o
C
0
=0 s So
4, ~ ~
_ _ _ Cat ~ ~
C,~3s
. . 4,
~ ~ _
0
a,
~s, ~ ~
0 ~ ~ o3
—0 at
oe
O ~ ~
2'2 0
0 0— 3 I:
a, ~ u, 0
a~ 0 0
0=
Ji
__
o'
0 0 a~
S0 o ~
C ~ 2 ~
C O O ~
O _ O i~
~ o s E
Bo
~ 0 °
a'
cn
~Q
V,
a'
~Q
;0
-
E ~ c ~s '
0 0 4, C o
o o ,,, o
o ~ ' c 2
a; - o
~ o '
E
0 0 s o
[L ~ C, Q
1
U~
~Q
00
-
o
U) -
Za)
o
OCR for page 103
103
There are two principal sources of information about the toxic
properties of chemical substances: investigations of exposed human
populations or individuals Epidemiological or clinical investigations
and experimental studies in laboratory animals or other biological
systems. Knowledge of the molecular structure of some substances may
be helpful in predicting toxic properties, but this aspect of
toxicological science is still immature (Asher and Zervos, 1977;
Klaassen and Doull, 1980; NRC, 1980b; OSTP, 1985) e
Data on Humans. Well-conducted Epidemiological and cl inical
investigations provide pertinent data for the evaluation of the
hazardous properties of environmental agents. Epidemiological studies
have provided convincing evidence about the cancer-causing properties
of such agents as cigarette smoke, asbestos, vinyl chloride, and
diethylstilbestrol (DES) and about the teratogenic effect of
thalidomide. Clinical investigations of exposed persons have provided
information on the toxicity of consumer and industrial products
(MacMahon and Pugh, 1970; OSTP, 1985~. There are, however, the
following limitations in the use of both Epidemiological and clinical
data for identifying the toxic properties of chemical substances:
· The deliberate, controlled exposure of human beings to identify
toxic effects is, with few exceptions , unethical. Exceptions
include short-term exposures to substances (e. g., certain
drugs) that produce mild, fully reversible effects.
Epidemiological and clinical studies cannot be conducted on
newly introduced chemicals or chemicals for which there has
been little or no previous human exposure.
Accurate data on the chemical nature of the substances to which
populations or individuals may have been exposed and on the
intensity and duration of their exposure are rarely available,
especially when exposures have taken place in the distant past.
It is difficult to provide proper controls for Epidemiological
studies when the cause-and-effect relationships of a chemical
cannot be easily established, as is the case for chemical
workers who may be exposed to unknown amounts of other
substances in addition to the chemical of immediate interest.
In investigations of diseases with long latent periods, such as
cancer, it is usually difficult to follow exposed persons for
periods long enough for the disease to reach a clinically
detectabl e state and thus for firm conclusions to be drawn
about the presence or absence of an effect.
Epidemiological studies cannot generally detect small but
possibly important changes unless the study population is very
large (rarely practicable) or the resulting disease is rare
(e.g., occurrence of vaginal adenocarcinoma during adolesence
in daughters of mothers given DES during pregnancy).
OCR for page 104
104
Because of these limitations, public health officials must
frequently turn to experimental data for information about the toxic
properties of chemicals in the environment.
Experimental Animal Data. Laboratory animal studies have an
advantage over epidemiological and clinical investigations (NRC,
1980b). The experiments can be controlled so that causal relationships
between exposure to a substance and toxicity can be established, and
the relationship between the intensity and duration of exposure and the
magnitude of toxicity can be studied (NRC, 1980b). (See section on
Dose-Response Assessment below.) Animals can be studied for functional
changes or killed at var' ous times during the experiment and examined
for the presence of a variety of biological injuries and pathological
changes that are not observable clinically. In rats and mice, the
effects of lifetime exposures to an agent can be detected in 2 or
3 years - - the normal lifespan of these species (OSTP, 1985 ~ O
These advantages of data from animal studies are partially offset
by the obvious fact that animals are not biologically identical to
humans. To conclude that some agent can cause a certain form of
toxicity in humans because it does so in laboratory animals requires
inclusion of some untested assumptions about the biological similarity
of various mammalian species. There is evidence that results from
animal studies are often applicable to humans. For example, most
substances known to be carcinogenic in humans are also carcinogenic in
animals. Similar examples could be collected for a variety of other
toxic effects (NRC, 1983; OSTP 9 1985 ~ . Exceptions are also common,
however .
Unless human data are adequate to refute a specific finding of
toxicity in animals or there is some other biological reason to do so,
it is reasonable to infer a potential for toxicity in humans from
observations in experimental studies of animals. Animal experiments
are the principal source of toxicity data for assessing the human risks
and safety of pesticides, food and color additives, and food and
drinking water contaminants, and there is no reason not to rely on such
data for similar assessments of chemical residues in poultry products.
Manifestations of Toxicity and Tests to Identify Them. Systematic
investigation of the toxicity of a chemical substance usual] y begins
with a determination of its acute toxicity, which includes a
determination of the dose of a substance that in a single exposure
(lethal dose) will cause the deaths of the exposed animals within a
short time after administration. At successively lower levels of
exposure, the percentage of animals that respond decreases
correspondingly. The relationship between dose and the percentage of
the animal population that dies is called the dose - response
relationship for the end point in question- - in this case, death. The
range of doses over which deaths are observed and the shape of the
dose-response relationship vary from one substance to another, and both
are critical to an assessment of a substance's capacity to cause death
in an exposed population.
OCR for page 105
105
Short-term exposures (i.e., one or several exposures repeated over
several days or a few weeks) to chemical substances in amounts lower
than the lethal dose may produce toxicity that ranges from mild (e.g.,
reversible eye or skin irritation or transitory nervous system
disorders) to severe (e.g., irreversible blindness or liver damage).
The toxic manifestations of a short-term exposure to a chemical depend
on the intensity and duration of the exposure and the characteristics
of the chemicals (Doull et al., 1980; Loomis, 1978; NRC, 1983~.
Studies of short-term exposures are generally followed by studies
of long-term exposures to lower doses (chronic toxicity)(NRC, 1980b).
These experiments are designed to detect effects that arise after many
repeated, sometimes daily, exposures that occur over various
periods - - from approximately 10% of an animal ' s lifespan (subchronic
toxicity studies) to its ful 1 lifespan (2-3 years for rodents; several
times longer for other commonly used animals such as dogs and monkeys)
or effects resulting from short- term exposures that do not become
clinically detectable until much later (e. g., for DES) . Chronic
effects may range from relatively mild conditions to progressive and
lethal lesions such as cancer . The form of inj ury or disease and its
dose-response characteristics are specific to the chemical, but both
these features of chemical toxicity can be altered by characteristics
of the exposed animal (e.g. 9 its genetic background, health status,
age, or sex) and its environment (e.g., the nature of its diet or the
presence of other environmental agents). Such interspecies and
intraspecies differences in toxic response and dose-response
characteristics for a given substance have strongly influenced the
methods used by public health scientists to assess risks. (See section
on Risk Characterization below).
Subchronic toxicity experiments can reveal much about the potential
of a substance to inj ure various organs and systems of the body,
including the developing fetus, but they cannot reveal whether a
substance can induce cancer (OSTP, 1985), except when it is unusually
potent. Determination of carcinogenicity usually requires that test
animals be exposed for most of their lifetimes.
There are now many well-validated test systems used worldwide by
both public health agencies and private concerns to establish the
acute, subchronic, and chronic toxicities of chemical substances (EPA,
1982; FDA, 1982b; NRC, 1977~. The most thoroughly tested substances
are those that must, by law, be evaluated before they can be introduced
into commerce (e.g., food and color additives, drugs, and
pesticides)(NRC 9 1985~.
Quality and Extent of Data. The quantity and quality of toxicity
data available on different substances vary greatly. For a few
substances the data base may be extensive and may include results of
all the standard toxicity tests as well as data specific to each
substance under evaluation, whereas for other substances, the data base
OCR for page 106
106
may include, at best, only a determination of acute toxicity or no
significant toxicity data at all. For most important industrial
chemicals, the quantity and quality of available data fall somewhere
between these two extremes, but more toward the lower end of the scale
(NRC, 1984~.
There is no straightforward way to define the adequacy of a given
data base. A data base may be sufficient to determine the safety of a
certain use or type of chemical exposure but may be inadequate to
determine the risk presented by another use or type of exposure. For
example, many agents tested for occupational risk have not been
examined for their potential to cause chronic toxicity or birth
defects. If such substances show up in the poultry supply because of
environmental pollution, the absence of information on chronic effects
and their effect on the developing fetus would be of great concern.
Similarly, the absence of chronic toxicity data on many chemicals is of
concern if the chemicals are found to be present in poultry products to
which people could be chronically exposed. The absence of data does
not imply that a risk exists, but it does mean that risk (and therefore
safety) cannot be ascertained with an adequate degree of confidence.
Various methods are used to compensate for such data gaps. These
methods are described below in the section on Risk Characterization.
Hazard Evaluation. This phase of risk assessment includes a
critical review of clinical 9 epidemiological, and experimental toxicity
data and identification of the inherent hazardous properties of a
substance, the degree to which these hazards are known, and the
uncertainties in the data. A critical feature of this process are
j udgments about the strength of inferences for human risk from data
derived from animal studies . At this stage of risk assessment, no
attempt is made to determine the degree of human risk that might be
associated with the substance under evaluation.
Dose-Response Assessment
For an exposure of a given duration, the frequency and severity of
toxic effects in an exposed population (the risk) generally increase
with increasing dose. Toxic effects may also change as exposure
increases. The dose-response relationship is critical to risk
assessment and must therefore be well defined. Well-defined
dose-response relationships can rarely be obtained from ep~demiological
studies because of uncertainty regarding the exposures that produced
the toxic responses seen. Therefore, experimental data are the primary
sources of dose - response information for risk assessment.
The dose of a toxic agent can be expressed in various ways. Most
commonly it is presented as the weight (mg) of the agent taken into the
body per unit (kg) of body weight (bw) of the human or test animal per
unit of time (usually, per day), e.g., mg/kg low/day. Dividing intake
by body weight permits comparisons to be made among species with
OCR for page 107
107
different average body weights. Other measures of dose, such as mg/kg
bw over a lifetime, mg/m of body surface area, parts per million
(ppm) in air, water, or diet, are used less often.
For most toxic effects, a threshold dose is the amount of exposure
that must be exceeded before a specific toxic effect is produced. For
other effects such as cancer, however, there appears to be a biological
basis for rejecting the threshold hypothesis. As currently practiced,
in fact, carcinogenic risk assessment is generally based on the
assumption that there is no threshold dose. Rather than entering more
fully i nto the complex debate on thresholds, the committee has simply
adopted the positions taken by the major regulatory and public health
agencies and other NRC committees , i. e., the absence of a threshold for
carcinogens .
A critical part of dose-response assessment is identification of
the dose that produces no adverse response, i.e., the no - observed-
effect level (NOEL), in the treated animals. The NOEL is generally
taken as the starting point for risk assessment of virtually all
effects other than cancer. It may approximate a threshold dose for the
animal population under study, but for a variety of reasons the
experimentally determined NOEL is probably not identical to the true
threshold dose.
For carcinogens (even those for which an experimental NOEL for
other toxic effects has been determined), the dose-response data are
treated differently. The size of the increase in toxic effects at
various low doses, where the risk per animal (and by extension, per
person exposed) is quite small, is generally of greatest interest but
not directly observable because of practical li mits on experi-
mentation. Carc~nogenicity data from animal studies generally show
that increasingly high doses cause a corresponding increase in the
incidence of cancers. However, the doses used in animals are
exceedingly high in terms of human risk to compensate for the fact that
only small numbers of animals can be used in experimentation of this
type (OSTP, 1985~. For example, if 50 animals are exposed to a dose of
a carcinogen and 5 develop tumors, the risk is 10% (if no control
animals develop a tumor). A cancer risk near 10% would be intolerable
in any human setting, but this is about the smallest risk that can be
reliably detected in animal experiments of practicable size (OSTP,
1985).
The experimentally determined relationship between dose and risk at
high doses must therefore be used to assess risk for dose levels
corresponding to human exposures. This requires the use of certain
mathematical models of the dose-response data (FSC, 1980; NRC, 1980b;
OSTP, 1985~. These models generally provide unit risk estimates, i.e.,
estimates of cancer risk per unit of dose (such as the incidence of
cancer at a dose of 1 mg/kg low/day over a lifetime). The models most
widely used for low dose carcinogenic risk assessment are based on
OCR for page 108
108
assumptions that there is no threshold and that risk at very low doses
increases in direct proportion to dose. Several models meet this
criterion. EPA uses the linearized multistage model, which
incorporates an upper 95% confidence limit on the estimated linear
term. Table 5-l presents risks per unit of low dose exposure predicted
by this model for substances that are potential contaminants of poultry
products. Models used by FDA and the National Research Council's Safe
Drinking Ilater Committee (NEt.C5 1980a) would yield unit cancer risks
close to those shown in Table 5-1.
It Is not possible to demonstrate that any mathematical models are
fully in accord with biological reality. Because this subject has been
discussed elsewhere (NRC, 1980a; OSTP, 1985), the committee simply
notes in this report that certain models are widely used in risk
prediction and that they are generally interpreted on the basis of
little direct evidence as providing upper limits on low dose risk,
although recent data suggest that this may sometimes be wrong (J. C.
Bailar, Harvard School of Public Health, personal communication,
1987~. Policy choices needed in the face of scientific uncertainty
have also been discussed in another National Research Council report
(NRC, 1980b).
The dose-response assessment phase of risk assessment thus
generally concludes with a determination of NOELs (for noncarcinogenic
effects) and of estimates of risk per unit dose (unit risks) for
cancers. In both determinations there are important uncertainties that
need to be specified in the report of the risk assessment. Since many
of these uncertainties concern the data on which these dose-response
estimates are based and are therefore chemical- specific, they must be
defined by experts who have studied a specific substance. Other
uncertainties are generic (e.g., some are inherent in models for
extrapolating from high to low doses) and therefore apply to all
chemicals.
Exposure Assessment
Exposure assessment is a highly complex subject, and is reviewed
here only to the extent necessary to prepare for the later discussion
of chemical residues in poultry products. In this phase of risk
assessment, knowledge of the magnitude and duration of human exposure
to environmental agents and, most importantly, the dose that results
from this exposure, is essential As used herein, the term exposure
describes a person's contact with a medium (e.g., poultry) containing a
chemical. The magnitude of the dose that results from the exposure
depends on several factors, which are described in the following
paragraphs O
To estimate dose, the possible routes of chemi cat ~ ntake must first
be identified. For residues in poultry, ingestion is the only route of
concern. Occupational exposures might include inhalation, derma]
contact, or other routes of exposure, but these routes are not germane
OCR for page 109
109
TABLE 5-1 Unit Cancer Risks and Strength-of-Evidence Categories for
47 Chemicals, as Evaluated by the EPA Carcinogen
Assessment Groupa
Level
of Evidenceb Unit Cancer Risk
. . .
Compound Humans Animal s per mg/kg bw/dayC
Acrylonitrile L S 0. 24(W)
Aflatoxin B1 L S 2, 900
Aldrin I L 11.4
Allyl chloride -- -- 1.19 x 10 2
Arsenic S I 15 (H)
Benzo ~ a ~ pyrene I S 11 . 5
Benzene S S 2.9 x 10-2(W)
Benz idene S S 2 34 (W)
Beryllillm L S 2 .6 (W)
Cadmium L S 6 . 1 (W)
Carbon tetrachloride I S 1. 30 x 10~
Chlordane I L 1.61
Chlorinated ethanes:
1,2-Dichloroethane I S 9.1 x 10-22
Hexachloroethane I L 1.42 x 10-
1,1,2,2-Tetrachloroethane I L 0.20 2
1,1,2-Trichloroethane I L 5.73 x 10-
Chloroform I S 8.1 x 10-2
Chromium VI S S 41(W)
Dichlorodiphenyltrichloroethane
(DDT) I S 0 34
Dichlorobenzidine I S 1.69
OCR for page 110
110
TABLE 5-1 (continued)
Level
of Evidenceb Unit Cancer Risk
Compound Humans Animals per mg/kg bw/dayC
Dieldrin ~ S 30.4
Ep~chlorohydrin I S 9.9 x 10-3
Bis(2°chloroethyl~ether I S 1.14
Bis~chloromethyl~ether S S 9,300(In)
Ethylene dibromide I S 41
Ethylene oxide L S 3.5 x lO~l(In)
Heptachlor I S 3 . 37
Hexachlorobenzene I S 1. 67
Hexachlorobutadiene I L 7.75 x 10-2
Hexachlorocyclohexane:
Technical grade ~ 4.75
Alpha isomer I S 11.12
Beta isomer I L 1.84
Gamma isomer I L 1.33
Nickel refinery dust S S 1.05(W)
Nitrosamines:
Dimethylnitrosamine I S 25.9(not by q )~
Diethylnitrosamine I S 43.5(not by q
Dibutylnitrosamine I S 5.43
N-Nitrosopy~rol~dine I S 2.13
N-Nitroso-N-ethylurea I S 32.9
N-Nitroso-E-methylurea I S 302.6
Polychlorinated biphenyls
(PCBs) I S 4.34
Phenols:
2, 4,6-Trichlorophenol I S 1.99 x 10-2
Tetrachlorodibenzo-~-dioxin
(TCCD) I S 1.56 x 10+5
OCR for page 129
129
If poultry feed and water limits are properly set and enforced,
there may still be occasional failures to keep residues within
tolerance levels. These failures may have only limited health
consequences, however, because tolerance limits for chronic exposure
include large safety factors. Although there is no precise definition
of an occasional failure, it should be assumed to mean rare occurrence
in the life of an individual.
When such excursions above tolerance levels are detected, it should
be determined whether they present any reason for concern about larger,
longer, or more frequent violations of standards. Each such finding
should trigger an effort to learn the cause of the problem and to find
a remedy. In the context of adequate feed and water controls, it is
not possible to predict how long such tolerance violations should be
allowed to continue before poultry or poultry products are condemned.
However, once a tolerance violation occurs, a risk assessment is needed
at times to identify the seriousness of the potential risk. A decision
could then be made on the need for condemnation as well as the need to
change the feed and water tolerances, alter the production process, or
intensify inspection.
Activity 7. Enforcement
Monitoring programs to manage risks are not effective unless they
can ensure that excessively contaminated poultry feed or water is not
used and that excessively contaminated poultry products do not reach
consumers. Regulatory agencies have long had programs of enforcement
to ensure that these objectives are met. The need for such programs is
obvious, and no additional justification need be given here.
Activity 8. Establishing Priorities
Any program based on Activities 1 through 7 will require
establishment of priorities. Two monitoring efforts (Activity 5, for
feed and water, and Activity 6, for poultry products) require the
development of sampling plans that can ensure, with some predetermined
degree of confidence, that risk-management objectives are being
achieved. As stated above, risk-management priorities and the
frequency and intensity of monitoring should be based on risk
assessment. For much risk-management planning, only the relative risks
of various substances are of concern. A methodology for assessing
relative risks is proposed in the following paragraphs.
Assessing Relative Risks
A scheme for assessing relative risks need not include estimation
of the absolute risk of any of the substances to be ranked. It is
necessary only that it incorporate in a systematic way some measures of
both toxicity and exposure that are as accurate as possible; risk
assessment cannot proceed without them. The exposure and toxicity data
OCR for page 130
130
on Class 1, 2, and 3 chemicals vary widely in quality and content.
These differences should be taken into account in a systematic way.
The primary purpose of a relative risk assessment is to ensure that
the two major risk-management activities (monitoring of feed and water
and monitoring of poultry products, including whole birds) achieve the
intended objectives. That is, the degree of risk-management attention
accorded a substance is directly related to the probability that it
will be found in food intended for human consumption and to the risk it
may pose if it escapes detection
Two useful measures for ranking relative toxicity are the ADI ~ for
noncarcinogens ~ and the UCR. These measures have the following
desirable characteristics.
They are derived from toxicity data in ways that are now rather
well standardized and accepted.
Different types of toxicity data gaps are treated in a
relatively uniform way for different substances, e.g., by the
application of standardized risk- assessment procedures.
These measures are based on chronic exposure.
They should be estimated for all substances monitored. (Recall
that surveillance i s used to identify substances for which risk
assessment and tolerances need to be established, whereas
monitoring is restricted to substances for which tolerances
have been established. ~
These two measures are adequate to rank the chronic toxicities of
Class 1 and 2 substances. The committee knows of no other measures
that have all the above characteristics.
To provide a systematic way of comparing carcinogens and
noncarcinogens, it may be necessary to develop a single toxicity scale
that integrates both categories of substances. It is possible to
derive an ADI equivalent for a carcinogen from its UCR by using certain
assumptions about the level of risk considered to be negligible and the
level of risk associated with an ADI for a threshold agent. Under the
assumptions used to derive UCRs, carcinogens present a nonzero risk at
all exposure levels above zero. Nevertheless, it is commonly accepted
that for all carcinogens there is an exposure ra5ge that6presents only
a small risk, e.g., lifetime risks less than 10- or 10- , which
reflect highly unlikely events O
It is not possible to demonstrate that an ADI carries absolutely no
risk for the human population. At best, all that can be claimed for an
ADI is that any potential risk is not likely to exceed some very small
but quantified risk In the absence of evidence to the contrary, and
to provide two different toxicity scales for carcinogens and
noncarcinogens, it may be assumed that the range of risk associated
with an ADI is the same as that as that considered to be very small
carcinogens ~ i . e ., 10 ~ 5 to 10 ~ 6 ~ . This assumption is presented
here only in the context of this specific risk-ranking obj ective to
OCR for page 131
131
provide a systematic means for comparing the toxicities of carcinogens
and noncarcinogens. It does not imply that the actual risk at an ADI
is in the range assumed here.
It is further assumed that an ADI for a noncarcinogen will ensure
that there is not more than a 10-6 (1 in a million) risk of a toxic
effect occurring. An ADI equivalent derived for carcinogens will be
taken as the dose estimated to give rise to the same maximum lifetime
risk (10-6~. The ADI equivalents for carcinogens can then be
directly compared to ADIs for noncarcinogens, because both will have
been adjusted for potency and represent the same estimated risk level.
Figure 5-2 presents the linear low-dose response of several
carcinogens with different UCRs. For each 6f these carcinogens, a dose
providing an estimated lifetime risk of 10- can be identified.
These ADI equivalents are represented by points for carcinogens A, B.
C, And D along the dose scale. Thus, a carcinogen (B) with a OCR of
10- per unit of dose measured in mg/kg low/day would have an ADI
equivalent of 0.001 mg/kg/day. A UCR of 10-7 (carcinogen D) would
correspond to an ADI equivalent of 10 mg/kg/day. These ADI equivalents
can be calculated for the entire range of published UCRs. A
representative range of ADIs and ADI equivalents and some possible
toxicity ranking scores are presented in Table 5-3.
Unfortunately, there appears to be no single, direct measure of
potential exposure. Thus , in constructing a ranking system for
exposures, many factors must be considered. For example, the following
factors all contri bute to potential exposure for Class 1 and 2
substances:
1. The portion of the ADI or other tolerable limit to which
people are ordinarily exposed. Frequent exposures to large fractions
of the ADI (through poultry products only or through several
environmental media) present higher potential risks than occasional
exposures to only a small fraction of the ADI. A tolerance violation
may have much greater significance for the former than for the latter
exposure .
2. The frequency with which the chemical is or is likely to be
detected in feed, water, or poultry products.
3. The volume of use for Class 1 substances and the volume of
production, industrial use, or natural occurrence for Class 2
substances .
4. The number of birds treated or otherwise exposed.
5. The propensity for bioacc~mulation.
OCR for page 132
132
l
o
_
l
in
o
or
C:
Sit
v
o
7
o
_
I\
to
; ~
lo lo 70 To lo lo lo,
_ _ _, _ _ ~ _ o
ASIA
-
° C,9
a
oo
, _
o
En ~-!
~ o
.> o
c) o
sit
H ,,4
˘ ~
o F=,
~ -
o
Cal
1
Us
OCR for page 133
133
Table 5-3. Chronic Toxicity Scoringa
ADI Range (mg/kg/day)
Toxicity Score
<10-7
210-7 <10~6
21o~6 <1o~5
210-5-<10-4
210-4-<10-3
210-3 <10~2
>1o-2-<
210~1 <1
2 1
9
8
7
6
5
4
3
2
1
aFrom Environ Corporation, 1985. For non-
carcinogens, use ADI; for carcinogens, use an ADI
equivalent,
than 10-6.
assuming a lifetime risk no greater
6. The frequency and magnitude of consumption of the mayor tissues
in which residues occur. (Substances accumulating in skin and muscle
are of greater concern than those present only in the lung or kidney.)
~ ,
FSIS should use these six factors to establish a ranking scheme for
chemical exposures. Generally, the range of possible scores for
potential exposure should approximately equal the range of toxicity
scores (i.e., toxicity and exposure should be given approximately equal
weight). One such scheme would be to assign a numeric score to each of
the six items: for example, a score of 1 or 2 for factors 1 and 5; a
score of 0, 1, or 2 for factor 3; and a score of 0, 2, or 4 for factors
2, 4, and 6. The total of these scores divided by 2 would yield
exposure scores ranging from 1 through 9. The overall priority ranking
system would then be based on a combination of this exposure score with
the toxicity score.
for examcle. a score of 1 or 2 for factors 1 and 5; a
Use of Relative Risk Scores.
ranking procedure, one should
By systematic application of this
able to establish priorities for
OCR for page 134
134
monitoring feed, water, and poultry products and to develop sampling
plans that are matched to the potential risks . The procedure shou1 d
also be useful in establishing ADIs and tolerances for residue levels
in poultry products.
Use of a single monitoring strategy for all chemicals would be
inappropriate, since adequate attention would not be given to
potentially high risk substances and too large a share of resources
would be devoted to low risk substances. A more appropriate scheme
would be based on first ranking the risk (e.g., high, medium, and low
risk) and then categorizing the chemicals according to the type of risk
they present (e.g., carcinogens, teratogens, liver toxicants).
Intensive monitoring programs should be devised for potentially
high-risk substances, less-intensive programs for those posing medium
risks, and minimal monitoring activity for low-risk substances. Of
course, ranking should be continually updated as new data emerge to
determine the need for regrouping.
Of particular importance for the two - stage monitoring strategy
described above is the choice of sampling rate. Statistical sampling
strategies can be devised to ensure, with a specified degree of
confidence, that products containing excessive levels of chemical
res idues are identified for removal from the food supply . The
desirable degree of confidence for a potentially high-risk substance
should be greater than for other substances. In Chapter 7, the
committee recommends criteria for sampling chemical res idues pos ing
different levels of potential public health risk.
Finall y, all eight essential activities of a risk-management
program for chemical residues are based on applying, with varying
degrees of rigor, the elements of a risk- assessment scheme based on
specific types of data. Although an effective risk-management scheme
will require all eight activities, not all of them need be under the
direct control of FSIS. Indeed, some activities are already
established at FDA and EPAo Nevertheless, to the extent possible, PSIS
should ensure that all eight activities are under way and are
adequately pursued.
SPECIAL PROBLEMS
As noted above, two aspects of chemical hazards in poultry require
special treatment: Class 4 substances (those formed during processing,
storing, and heating) and metabolites and degradation products of
chemicals .
Class 4 Substances
The information needed to perform risk-assessment activities 1
through 3 for Clas s 4 subs tances is the same as that required for
Classes 1, 2, and 3, but there are few data on the potential public
OCR for page 135
135
health risks presented by these chemicals. For example, it appears
that there has been no comprehensive risk assessment for any of these
substances found in table-ready broiler chickens. Because Class 4
substances contaminate poultry products by mechanisms different from
those for Classes 1, 2, and 3, it is not clear whether the risk-
management strategies described for those classes are appropriate for
Class 4. The committee believes it would be premature to devise a
comprehensive risk-management strategy for them and recommends that
FSIS initiate efforts to assess their risks in a comprehensive manner.
Metabolites and Degradation Products
In the regulation of residues in poultry, most attention has been
given to the parent compounds administered to or ingested by the bird
rather than to the' r metabolites or degradation products. EPA and FDA
have given some consideration to those products, but it is not clear to
the committee that the two agencies have treated the subject adequately
or consistently.
There are no data indicating that metabolites or degradation
products pose significant risks that are unregulated or that the risks
of these products, to the extent they are considered, are under- or
overestimated by the agencies. It nevertheless seems important to
examine this issue carefully and to evaluate its present status.
ASSESSING PUBLIC HEALTH RISKS OF CHEMICAL RESIDUES IN POULTRY PRODUCTS
The magnitude of the public health risk from chemical residues in
poultry products has not yet been examined, but the committee believes
it important that such risk assessments be undertaken routinely. The
chemical residue data developed by FSIS (Table 5-2) are not by
themselves adequate for risk assessment, because the following
information is lacking:
· the quantitative relationship between the levels of residues
found in specific tissues examined by FSIS and the levels
present in all other edible tissues;
the amounts of different poultry products consumed by different
segments of the population;
the capability of the analytical methods used to detect
residues below a certain level of contamination;
toxicity data, ADIs, and UCRs for each residue;
the level of human exposure resulting from other environmental
media in which residues of the same chemicals may be present;
and
time trends in contamination patterns.
The information necessary to perform residue-specific risk
assessments is available for many substances, especially those in
Class 1. Access to FDA and EPA data files will be necessary to acquire
OCR for page 136
136
the necessary toxicity and tissue distribution data and to estimate
background levels. FSIS residue data should be analyzed statistically
to determine the extent to which they are representative of the poultry
product supply as a whole. These are tasks that can be completed with
varying degrees of thoroughness for different residues. They should
nevertheless be undertaken for all commonly found residues, but extreme
care must be taken to ensure that the limitations in the data base and
in the risk-assessment methodologies used are clearly set forth.
Qualitative risk assessments should always be accompanied by
descriptions of their limitations.
Because compliance with current tolerances for Class 1 chemicals is
relatively high, it is likely that risk assessments undertaken for them
will result in very low risk estimates. However, compliance with
prescribed tolerances does not necessarily ensure low risk 9 since the
adequacy of the data base for Class 1 substances has not been reviewed
and there may be significant data gaps or limitations. Many substances
in Class 1 were approved or registered by FDA and EPA many years ago;
however, the committee knows of no routine federal effort to ensure
that the data base for these substances meets current standards, except
for limited EPA efforts with regard to some pesticides. It would thus
be necessary to review the toxicity data base for Class 1 substances
before accurate risk assessments can be completed.
The data base for Class 2 substances is certain to be less adequate
than that for Class 1 substances It is not even clear that all
important chemicals in Class 2 have been identified. Nevertheless,
risk assessment for Class 2 substances should be undertaken and
limitations in data and methodology described to the extent possible
with current ;nfo'=ation. It is particularly important to include
information on other environmental sources of exposure to these
chemicals, such as PCBs and some of the widely dispersed chlorinated
hydrocarbon pesticides, so that the contribution of poultry products to
total risk can be understood and the information can be used to
estate ish special control programs where high risks exist and to reduce
or eliminate programs now focusing on trivial problems. Although the
committee examined the data and found no evidence of significant public
health risks attributable to chemical residues in broilers, risk
assessments and data are needed before definitive conclusions can be
reached.
REFERENCES
Asher, I. M., and C. Zervos, eds. 1977. Structural Correlates of
Carcinogenesis and Mutagenesis. A Guide to Testing Priorities?
Proceedings of the Second FDA Office of Science Sumner Symposium
held at the U.SO Naval Academy, August 31-September 2, 1977. DREW
Publ. No. (FDA) 78-1046 O The Office of Science, U.S. Food and Drug
Administration, Rockville, Md. 241 pp.
OCR for page 137
137
Calabrese, E. J. 1983. Principles of Animal Extrapolation. Wiley,
New York. 603 pp.
CFR (Code of Federal Regulations). 1986. Title 21, Food and Drugs;
Section 520.2240a, Sulfaethoxypyridazine drinking water. U.S.
Government Printing Office, Washington, D.C.
Doull, J., C. D. Klaassen, and M. O. Amdur, eds. 1980. Casarett and
Doull's Toxicology--The Basic Science of Poisons, 2nd ed.
Macmillan, New York. 778 pp.
Environ Corporation. 1985. Documentation for the Development of
Toxicity and Volume Scores for the Purpose of Scheduling Hazardous
Wastes. Prepared for the Office of Solid Waste, U.S. Environmental
Protection Agency. EPA Contract No. 68-01-6861, Subcontract No.
38-9. Environ Corporation, Washington, D.C. 130 pp.
EPA (Environmental Protection Agency). 1980. Water quality criteria
documents; availability. Notice cuff water quality criteria
doc~ents . Fed. Regist. 45: 79317-79379 .
EPA (Environmental Protection Agency). 1982. Pesticide Assessment
Guidelines, Subdivision F , Hazard Evaluation: Human and Domestic
Animals . Publ . No . EPA 540/9 - 82 -025 . Office of Pesticide
Programs, Office of Pesticides and Toxic Substances, U.S.
Environmental Protection Agency, Washington, D.C. 163 pp.
Available from the National Technical Information Service in
Springfield, Va ., as PB83 -153916 .
EPA (Environmental Protection Agency). 1985. Health Assessment
Document for Chloroform: Final Report. Publ. No.
EPA/600/8-84/004F. Office of Health and Environmental Assessment,
U.S. Environmental Protection Agency, Washington, D.C. [415 pp.]
Available from the National Technical Information Service in
Springfield, Va., as PB86-105004.
FDA (Food and Drug Administration). 1979. Polychlorinated biphenyls
(PCB's); reduction of tolerances. Final rule. Docket No.
77N-0080. Fed. Regist. 44:38330-38340.
FDA (Food and Drug Administrations. 1982a. D&C Green No. 6;
li sting as a color additive in externally applied drugs and
cosmetics . Final rule . Docket No . BIN- 0301 . Fed. Regist O
47: 14138 - 14147 .
FDA (Food and Drug Administration). 1982b. Toxicological Principles
for the Safety Assessment of Direct Food Additives and Color
Additives Used in Food. Bureau of Foods, U. S . Food and Drug
Administration, Washington, D. C. ~ 248 pp . ~
OCR for page 138
138
FDA (Food and Drug Administration). 1985. Sponsored compounds in
food producing animals; criteria and procedures for evaluating the
safety of carcinogenic residues. Proposed rule. Docket No.
77N-0026O Fed. Regist. 50:45530-45555
FSC (Food Safety Council). 1980. Proposed System for Food Safety
Assessment. Final Report of the Scientific Committee of the Food
Safety Council. Food Safety Council, Washington, D.C. 160 pp.
Klaassen, C. D., and J. Doull. 1980. Evaluation of safety:
Toxicologic evaluation. PpO 11-27 in J. Doull, C. D. Klaassen, and
M. 0. Amdur, eds. Casarett and Doull's Taxicology--The Basic
Science of Poisons, 2nd ed. Macmillan, New York.
Lehman, A. J., and 0. G. Fitzhugh. 1954. lOO 'ford margin of safety.
Assoc. Food Drug Off., Q. Bull. 18: 33-35.
Loomis, T. A. 1978. Essentials of Toxicology, 3rd ed. Lea &
Febiger, Philadelphia. 245 pp.
MacMahon, B., and T. F. Pugh. 1970. Epidemiology: Principles and
Methods. Little, Brown, Boston. 376 pp.
Nisbet, I. C. T. 1981. The role of exposure assessment in risk
evaluation: Research needs. Pp. 419-429 in C. R. Richmond 9 P. J.
Walsh, and E. D. Copenhaver, eds. Health Risk Analysis,
Proceedings of the Third Life Sciences Symposium. Franklin
Institute Press, Philadelphia.
NRC (National Research Council). 1977. Drinking Water and Health.
Report of the Safe Drinking Water Committee, Advisory Center on
'[oxicology. National Academy of Sciences, Washington, D. C.
939 pp.
NRC (National Research Council). 1980a. Drinking Water and Health,
Vol. 3. Report of the Safe Drinking Water Committee, Board on
Toxicology and Environmental Health Hazards. National Academy
Press, Washington, D.C. 415 pp.
NRC (National Research Council). 1980b. Risk Assessment/Safety
Evaluation of Food Chemicals. Report of the Subcommittee on Food
Toxicology, Committee on Food Protection, Food and Nutrition
Board. National Academy Press, Washington, D. C. 36 pp.
NRC (National Research Council). 1983. Risk Assessement in the
Federal Government: Managing the Process. Report of the Committee
on the Institutional Means for Assessment of Risks to Public
Heat th, Commission on Life Sciences. National Academy Press,
Washington, D-C- 203 ppO
OCR for page 139
139
NRC (National Research Council). 1984. Toxicity Testing, Strategies
to Determine Needs and Priorities. Report of the Steering
Committee on Identification of Toxic and Potentially Toxic
Chemicals for Consideration by the National Toxicology Program,
Board on Toxicology and Environmental Health Hazards. National
Academy Press, Washington, D.C. 395 pp.
NRC (National Research Council). 1985. Meat and Poultry Inspection:
The Scientific Basis of the Nation's Program. Report of the
Committee on the Scientific Basis of the Nation's Meat and Poultry
Inspection Program, Food and Nutrition Board.
Press, Washington, D.C. 209 pp.
National Academy
NRC (National Research Council). 1986. Drinking Water and Health,
Vol. 6. Report of the Safe Drinking Water Committee, Board on
Toxicology and Environmental Health Hazards. National Academy
Press, Washington, D.C. 457 pp.
OSTP (Office of Science and Technology Policy). 1985. Chemical
carcinogens; a review of the science and its associated principles,
February 1985. Final document. Ped. Regist . 50 : 10372 - 10442 .
Rodricks, J., and M. R. Taylor. 1983. Application of risk assessment
to food safety decision making. Regul. Toxicol. Pharmacol.
3:275-307.
Representative terms from entire chapter:
drinking water
