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| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
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OCR for page 51
II
Inference GuideNnes
for Risk Assessment
INTRODUCTION Al DEFINITIONS
An inference guideline* is an explicit statement of a
predetermined choice among the options that arise in
inferring human risk from data that are not fully ade
quate or not drawn directly from human experience. A
guideline might, for example, specify the mathematical
model to be used to estimate the ef feats of exposure at
low doses from observations based on higher doses. The
most Important feature of guideline use i s that it change s
the risk assessment process from one In which inference
options are selected on a substance by-substance basis to
one in which they are selected once and thereafter
*The Committee hopes to avoid any misunderstanding result-
ing from its use of the terms inference guideline and
guideline (used for brevity in lieu of inference quide-
l~ne). This terminology is potentially confusing, because
Guidelines cat be understood as codified principles ad-
dressed to a particular subject matter, risk assessment,
or as describing the legal weight of any codified stand
cards or principles. For the Committee, it has the former
meaning. Inference guidelines are the principles followed
by risk assessors in interpreting and reaching judgments
based on scientific data. (Thus, our inference guides
lines are d, stinct from the standards for toxicologic and
other testing standards that many regulatory agencies and
sc, entif ic bodies have adopted to govern, or at least
influence, the generation of data later used in risk
assessment. )
For many lawyers, the term guideline connotes the
weight to be given to any set of codified principles, not
~1
OCR for page 52
~2
applied to an entire series of chemicals. In the absence
of guidelines, assessors may well select the same infer-
ence options for substance after substance in a given
agency program, and a common set of inference options may
emerge, In canon law fashion, from their consistent
application In the program. But even the continued use
of the same set of inference options over time does not
necessarily imply that the assessors would make the same
choices for every substance. Furthermore, outsiders
would have no way of knowing what the common set is. In
contrast, the use of guidelines makes more evident the
generic choice oF inference options, which we have seen
in Chapter 7, is based on both scientific and risk
assessment policy considerations.
HISTORY OF 'Gil USE OF GUIDErINES
~~F~.~v ~V~1nATION GUIDELINES FOR ~
The development and use of guidelines by a regulatory
agency first became of major importance after Congress
only those addressed to risk assessment, in legal pro-
ceedings. The Food and Drug Administration, for example,
has defined a guideline as an official pronouncement of
the agency describing a procedure that satisfies legal
requirements, but is not mandated by law. A more complete
treatment of the distinction between binding regulations
and other formal agency pronouncements appears in the
section of this chapter entitled Degree to Which Guide-
lines May Be Binding on an Agency and a Regulated Party.
Tne Committee has used the term guideline to describe
the principles by which risk assessments are to be per-
formed, because that is the term Congress used in the
legislation that authorized this study. The Committee
was asked to consider the feasibility of establishing
uniform frisk assessment guidelines." There is no ev~-
dence that Congress was aware of the different meanings
of the term. It obviously was seeking advice about the
intellectual and scientific bases for codified principles
for risk assessment, not the appropriate legal form for
their adoption. Faced with possible confusion no matter
which terminology it chose, the Committee has retained
the language that Congress itself used to describe our
inquiry.
OCR for page 53
~3
enacted amendments to the Federal Food, Drug, and Cos-
metics Act in the 1950s and early 1960s. These laws, as
applied to noncarcinogenic agents, required that food
additives, color additives, drugs for animals, and pesti-
cides be shown to be safe under their intended conditions
of use before premarket approval by the Food and Drug
Administration (FDA). The agency developed guidelines to
provide a systematic way to deal with the legal requires
meets embodied in the amendments. Although guidelines
for the conduct of various types of toxicity tests
received greatest notice, some attention was given to the
problem of data interpretation for inferring human risk.
For example, a 1959 publication written by several members
of the FDA Division of Pharmacology, Appraisal of the
Safety of Chemicals in Foods, Drums, and Cosmetics, is
devoted primarily JO toxicity testing methods, but cons
tains one chapter called Some Interpretative Problems in
Evaluating the Safety of Food Additives. (Lehman et al.,
1959). Although that publication, which served as a
guide for both FOA and the regulated industry for at
least a decade, was never published as a regulation, it
was widely accepted by affected industrial concerns.
In all cases except that of carcinogens, establishment
of acceptable intakes was accomplished by applying saf ety
factors to experimentally derived no~observe~effect
exposures. Testing involved mostly the use of acute and
subchronic (90-day) animal tests, although some long-term
tests were required. The use of safety factors to estab-
lish acceptable intakes was also recommended by the Food
Protection Committee-of the National Research Council
(ENS, 1970) and adopted by the Joint Food and Agri-
cultural Organization and World Health Organization
Expert Committees on Food Additives (1972) add Pesticide
Residues (1965). This approach continues to be used for
noncarcinogenic food additives and pesticides and, in
slightly modified form, to define acceptable exposures to
occupational and various environmental pollutants.
These methods of assigning acceptable limits of expc-
sure imply that the application of safety factors of
various magnitudes to experimentally derived no-observed-
effect em osures will ensure low risk. The acceptable
exposure, whether expressed as an acceptable daily intake
for a food additive or as a permissible exposure limit
for an occupational agent, is derived by imposing untested
assumptions (e.g., about the likely nature of dose
response relations at low doses3 and by drawing inferences
from sparse data. Safety evaluation schemes Inky therefore
OCR for page 54
54
be classif fed as a set of guidelines that e~hasi ze test-
ing methods heavily and that afford methods of inference
only scant attention.
Recent efforts have dealt more directly with developing
guidelines for risk assessment of noncarcinogenic effects.
The Environmental Protection Agency (EPA) has proposed
guidelines for chemical mutagenesis (EPA, 1980a) and has
collected public ancients on them, but has yet to publish
a f inal rul e. In addition, Me agency cosponsored two
conferences with Oak Ridge National Laboratory on risk
assessment methods for reproductive and teratogenic
effects; the proceedings of the conferences have been
published (ORNL/EPA, 1982). The Interagency Regulatory
Liaison Group began to develop guidelines for risk
assessment of reproductive and teratogenic effects, but
the effort ceased with the disbanding of the group in
1981. The March of Domes Birth Defects Foundation (1981)
has published the proceedings of a conference dealing
with guidelines for studies of Herman populations exposed
to mutagenic and reproductive hazards. Despite the
increasing interest in noncarcinogenic effects, methods
of estimating the risk of these effects have not been the
subject of major public and scientific debate; attention
has been devoted mainly to carcinogenic risk assessment.
Much more critical review of the inferential methods for
assigning risks to noncarcinogenic agents is warranted.
GUIDELINES FOR CARCINOGENIC RISI;
Ontil the late 1950s, few agents, either chemical or
physical, had been regulated in this country on the basis
of their carcinogenic action. One important regulated
agent was ionizing radiation. Permissible exposures to
radiation were set in a manner similar to that for noncar-
cinogenic agents, by application of safety factors applied
to specified exposures. In the debate over health effects
of radioactive fallout from atomic weapons tests in the
l95Os, evidence to support a nonthreshold theory for
cancer induction emerged. Evidence was also accumulated
to indicate that the nonthreshold theory might be appli-
cable to chemical carcinogens. It was in this context
that Congress enacted statutes* in the 1950s and early
l
*The enactment of these statutes did not necessarily
bring a unique new concept to FDA. In the early 1950s,
OCR for page 55
~5
1960s that required FDA to ban Me use of food and color
additives shown to be carcinogenic. The aSsm~tion,
which differed from that underlying safety evaluation of
noncarcinogens, was that no exposure could be presumed
safe. Thus, a full risk assessment scheme was not needed
for carcinogens.
identification.
The process stopped at hazard
Many factors contributed to the later use of dose-
response assessment, exposure assessment, and risk char-
acterization to determine quantitative estimates of risk.
One of these may have been the growing perception during
the 1960s and 1970s that many kinds of risk could not be
eliminated completely without unacceptable social and
economic consequences. New laws reflecting this belief
were enacted, and some agencies were required to balance
the risk posed by carcinogenic agents against their per-
ceived benefits. Quantitative risk assessment was the
system developed to estimate the risk side of the bal-
ance. Over a period of 2 decades, various expert come
mittens sponsored by government agencies and other
organizations published numerous reports dealing with
carcinogenicity evaluation. Most of these were state-
of-the art reports on aspects of carcinogenicity ~nfer-
ence, and many suggested guidelines for hazard identifiers
tion. More recent reports have dealt explicitly with
quantitative risk assessment. The impetus for producing
these reports was probably a belief in the federal re-
search and regulatory communities that some scientific
principles related to carcinogenic~ty data evaluation had
to be continually reexamined and reaffirmed. This belief
pervaded the public-health establishment not only in the
United States, but also in other countries and in the
United Nations.
The following discussion examines efforts to develop
and apply guidelines for the evaluation of carcinoge-
nicity data by the federal regulatory agencies and the
International Agency for Research on Cancer over the last
decade--efforts that developed out of 2 decades of
scientific consensus-building.
before the' ~ enactment, the agency had prohibited three
food additives on the grounds that they were found to be
carcinogenic in test animals.
OCR for page 56
56
International Agency for Research on Cancer (IARC)
In 1971, the International Agency for Research on Cancer
(IARC), an agency of the World Bealth organization, began
publication of a series of monographs on known and sus-
pected carcinogens. These monographs are prepared by
international groups of experts assembled by IARC, who
critically review pertinent literature and draw conclu-
sions regarding the carcinogenic~ty of various substances.
The results of IARC reviews and evaluations are widely
accepted. The guidelines used for evaluation by the IARC
expert committees are set forth in the monographs. They
= ~ a ~
are expressed in very general berms gnu "~= `~ "~
, ~ ~
only six components of hazard identification, completely
covered in six pages of text.
A major feature of the
guidelines is the presentation of criteria that classify
the evidence of suspected carcinogens as surf icient or
limited. The IARC allows the expert committees consid-
erable latitude to evaluate many inference options on a
case-by-case basis, although the agency appears to insist
on adherence to the few stated guidelines.
Food and Drug Administration
The 1958 Food Additives Amendment to the Food, Drug, and
Cosmetics Act prohibited the use of Food additives found
to be carcinogenic. The law was also interpreted as
prohibiting MA approval of any drug, for use in animal s
produced for human food, that had been shown to cause
cancer. In 1962, by congressional amendment, EDA was
permitted to approve the use of a carcinogenic animal
drug ~f tne agency was convinced that no residue of a
drug would be found in edible tissues of the treated
animals. Congress specified that FOA was to prescribe
the analytic methods for verifying the absence of
residues. This directive proved to be unworkable, for
. _ ,
two reasons: progress In analytic chemistry was so Haiku
that approved methods of analysis quickly Became ODSo~e~e
and improved detection methods showed that no drug admini-
stered to animals is ever entirely absent from animal
tissues. The problem of enforcing the 1962 amendment was
highlighted in the early 1970s, when die~Ylsti~estrol
residues were discovered in beef liver with highly sew
sitive, but as yet unapproved, analytic methods.
In an attempt to provide a consistent and predictable
procedure for approving methods to search for drug resz-
OCR for page 57
~7
dues, FDA proposed sensitivity-of-method guidelines in
the form of regulations (FDA, 1973, 1977, 1979b). Rather
than gear criteria to an analytic technique, the agency
def fined its standards in terms of r isk. It proposed that
any assay approved for controlling a carcinogenic drug
must be capable of measuring residues that present more
than an insignif icant risk of cancer, and specif fed a
10-6 lifetime risk of cancer as a quantitative criter-
ion of insignificance. If a drug sponsor could provide a
detection method capable of measuring residues posing a
risk of this magnitude or greater, FDA would ignore resi-
dues that could not be detected with this method. Thus,
FDA found guidelines for quantitative estimation of risk
necessary. FDA's sensitivity-of-method guidelines are
unique in several ways. They address a narrow though
complex set of issues encountered in regulating a single
class of products, animal drugs. Although they deal to ~
large extent with testing, they were the first to address
quantitative risk assessment methods, listing assumptions
for dose~response assessment, exposure assessment, and
risk characterization. And they are the only guidelines
that att^ - t to establish a definition of significant
risk. The guidelines have yet to be adopted, a decade
.
after they were first proposed, but the agency has applied
the methods of quantitative risk assessment embodied in
the sensit~vity-of-method document in connection with the
regulation not only of animal drugs, but also of food
contaminants, such as aflatoxin (EDA, 1979a) and trace
constituents of some additives (EDA, 1982~). The
sensit~v~ty-of-method guidelines were proposed as regu-
lations, as were the cancer guidelines of the Occupational
Safety and Bealth Administration (OSElA). In both cases,
regulation engendered substantial controversy. The major
debate over the sensitivity-of-method guidelines has dealt
not so much with risk assessment or the definition of
significant risk as with the amount and cost of testing
that FDA would require from industry before product
approval.
Environmental Protection Agencv
During the early to middle 1970s, EPA initiated actions
to prohibit or restrict the use of several pesticides.
The agency lacked internal procedures for assessing
carcinogenic risk and relied heavily on the judgment of
scientists outside EPA. Attorneys for EPA, in summar-
OCR for page 58
~8
icing the testimony of their expert witnesses during
administrative hearings on actions against the pestz-
cides, set forth several statements that, in the legal
brief, were referred to as cancer print (EPA, 1972,
1975). They conveyed the idea that the only acceptable
degree of regulation would be a total ban on exposures.
The principles, perceived as EPA's cancer policy, incurred
wide criticism from the scientific community, the private
sector, and Congress. The Practicability of achieving
Cow rick On a broad scale for a large number of economi-
cally important chemicals became increasingly apparent.
In response to this new perception, and perhaps out of a
desire to avoid misunderstanding of its cancer policy,
the EPA became the first agency to adopt formal guidelines
embracing a two-step process of risk assessment (EPA,
1976). The first step is a determination of whether a
particular substance constitutes a cancer risk (hazard
identification). The second step is a determination of
what regulatory action, if any, should be taken to reduce
the ~ 1stc . As part of the second step, the agency explicit
itly endorses the use of quantitative risk assessment as
the means of determining He magnitude of the likely
impact of a potential human carcinogen on public health.
These guidelines were not published as regulations and
"niov fairly wide acceptance from most interested par-
_ , ~
ties. As stated in the preface to the guidelines, they
were published to Improve agency procedures, to provide
public notice of the approach that EPA would take, and to
stimulate commentary from all sources on that approach.
The guidelines were probably more important as a state-
ment of a novel approach to risk assessment than for their
content. They are grate general, cover less than a page
of Federal Resister text, and address only a few co~po-
nents of hazard identification, dose-response assessment,
exposure assessment, and risk characterization. More
detailed guidelines that specify assumptions for the
choice of extrapolation models, scaling factors, and
other elements of dose~response assessment were published
in 3980 by program offices in EPA (ERA, 1980~). These
rely in part on the Interagency Regulatory Liaison Group
(IRKING) guidelines {IBLG, 1979a) and are currently
undergoing review.
recall - Final s:~fetv and Health Admit
In 1977r OSEA published guidelines in a proposed regular
tion, ~Identification, Classification, and Regulation of
OCR for page 59
~9
Toxic Substances Posing a Potential Occupational Risk of
Cancers (OSBA, 1977); after extensive administrative
hearings, it published a final rule in 1980 (OSHA, 1980).
The guidelines proved to be highly controversial, and the
hearings were marked by vigorous debate on almost every
component of risk assessment covered by the guidelines.
The OSEA rule, written by agency staff, was a detailed
scientific and regulatory document that took several hunt
dred pages of Federal Register text and addressed almost
every component of hazard identification.
The final rule
did not address exposure assessment and red ected the use
of dose~response assessment for any regulatory purpose
except priority-setting. The main purposes of the guide-
lines. as stated in the preface, were to streamline the
process of risk assessment, to speed up regulation, and
to reduce the workload of agency staff. Another purpose
was to foster continuity of approach, even in the face of
changes of poll cy-makers. OSE1A stat f perceived that the
case~by-case approach to risk assessment was long and
t~e-consuming, because the same controversial questions
had to be argued each time a chemical was under cons~d-
eration for regulation. The agency believed Mat the
generic approach to risk assessment would reduce debate
on these questions; the controversial issues could be
decided once, incorporated into guidelines, and applied
to all chemicals. For reasons of efficiency, the guide-
lines.were written in language that permitted little
deviation from the judgments embodied in them. Because
they were written as regulations, regulated parties were
required to abide by them. The agency has not used the
rule as a basis for any published scientific assessment
of carcinogenic hazard. It was revised in 1981 (OSAKA,
1981) to accommodate the Supreme Court's ruling on ben-
zene, which required that OLGA make a finding that the
risk to workers in the absence of regulation was s~gnifi-
cant and would be reduced by the proposed standard. But
this change and additional amendments were recently with-
drawn, and the entire policy is under reconsideration
(OSEA, 1982).
~ , ~ ,= ~
Consumer Product Safetv Commission
The Consumer Product Safety Commission (CPSC) proposed
cancer guidelines dealing mainly with hazard identifica-
t~on (CPSC, 1978). Ten components related to that step
were addressed in several pages of Federal Resister text.
OCR for page 60
60
Some minor attention was Given to exposure assessment and
dose-sesponse assessment, for przority-setting purposes
only. The rationale for publishing the guidelines, as
stated in the preface of that document, was to establish
CPSC's general principles and to solicit comments on them,
to assist the general public and the regulated industries
in understanding standards that CPSC would apply and reg-
ulatory actions that it was likely to take, and to set
forth its approach to some issues that tended to recur i n
each case. The guidelines had no regulatory status; they
were a statement of selected inference options to which
the agency would adhere. The CPSC guidelines were never
used; they were challenged In court, and the court ruled
that CPSC had promulgated them illegally inasmuch as they
were adopted without an opportunity for public comment.
Furthermore, at that tome CPSC had decided to rely on the
guidelines of IRLG.
Interagency Regulatory Liaison Grout
The four agencies represented in IRLG undertook the task
or developing guidelines to n ensure that the regulatory
agencies evaluate carcinogenic risk consistently. n In
1979, after an 18-month interagency effort, FROG pub-
l~shed a report, unscientific Bases for Identification of
Potential Carcinogens and Estimation of Risk.. The report
was prepared by personnel of CPSC, EPA, For, and OSHA,
with the assistance of senior scientists from the National
Cancer Institute and the Nationa} Institute of Environs
mental Health Sciences. It was published in a scientific
journal (IRLG, 1979~) and in the Federal Register (IRLG,
1979a); IRVING requested public comment in the Federal
Register. The IRVING report was said to represent an inter-
agency consensus on Me scientific aspects of carcinogenic
risk assessment.* It was the most comprehensive set of
guidelines that had been developed for agency use, addres-
sing most components of hazard identification and dose-
~esponse assessment with some general discussion of
*Because rule~making was under way in connection with its
cancer policy, OSLO declined to participate in the IRKING
notice and comment procedure. After the report was
completed, the Food Safety Quality Service of the O.S.
Department of Agriculture joined IRKING and participated in
the notice and comment.
OCR for page 61
61
osure assessment and risk characterization; it had,
however, no official legal status. The report was note-
worthy, in that it constituted the first evidence that
all the federal regulatory agencies agreed on the infer-
ence options applicable to the identification of carcin-
ogenic hazards and measurement of risks. The document
made clear, however, that not all the agencies were bound
to conduct quantitative assessments; it stated only that,
if such assessments were to be conducted, they would be
conducted uniformly. This language was probably a cone
cession to OSBA's view, as expressed in its cancer policy,
that quantitative risk assessment was to play no more
than a priority-setting role in that agency's regulatory
activities. Almost immediately after its publication,
the IRLG report was adopted by the Pres~dent's Regulatory
Council and incorporated as the scientific basis of the
Council's government-wide statement on regulation of
chemical carcinogens. The Council viewed the IRLG guide-
lines as a major step in reducing inconsistency, dupli-
cation of effort, and lack of coordination among agencies
in carcinogenic risk assessment (Regulatory Council,
1979).
The scientific aspects of the final OSBA cancer policy,
which was written to allow less latitude in the choice of
inference options, were, nevertheless, za general agrees
ment with the I=G guidelines. CPSC and EPA stated that
they relied on the IN'G document, but the degree to which
they rely on it today is not clear. FDA }was made no
statement other than that associated with Me document's
initial publication; in fact, in a recent proposal con-
cerning the application of risk asses~'ent to a class of
trace constituents of additives, F ~ die not even cite
the IRLG document as a reference (FDA, 1982b). Although
IRLG received a great deal of public comment on the guide
lines, no report of the agencies' review of these comments
has appeared. In fact, the document was heavily critz-
cized by industry, because it was published In its final
form and adopted before the c~ents could be analyzed
and revisions incorporated. The Reagan Administration
has off icially disbanded the entire 7BLG effort, so it Is
unlikely that review of the public comments will ever
occur.
Although the IRLG charter was not renewed, a similar
group has been established, but one that is coordinated
by the White Bouse Office of Science and Technology
Policy. This group has prepared a draft document on the
scientific basis of risk assessment and has distributed
OCR for page 75
75
hiqh-dose testing. Critics believe that validity should
depend on whether there is a pharmacokinetic difference
between high and low dose. Special consideration should
be given to whether detoxifying or repair processes are
saturated and to whether competing metabolic pathways are
involved and become saturated.
Another potential problem is the lack of attention to
weighting of evidence. For example, a guideline may
simply state that appositive results in animal tests
should always outweigh negative results. This does not
take into account the quality and statistical power of
the different tests; i- -~1a Fonder the anti tude that
such considerations are of minor Importance.
To a large extent, the strength of such criticisms
depends on the form and contents of the guidelines.
Those which are comprehensive and leave little latitude
for exceptional cases tend to maximize the problem of
oversi~pl~f ication; those which are f lexible could be
most effective in mitigating the problem.
In addition,
guidelines may explicitly direct the assessor to consider
the weight of evidence of a given test result. For
example. the IRLG guideline stated that positive results
~ _ . _ = a _ = ~ = _
should supersede negative results, out aauea a caveat ;
n If the positive result is itself not fully conclusive or
if reasons exist for c~estzon~ng Its validity as evidence
of carcinogenicity, Me result is generally classified as
'inconclusive' or 'only suggestive' even in the absence
of other negative results. ~
Detailed guidelines can reduce the possibility of over-
simnlif ~ cation if the intent of detail Is to capture for
the assessor the cc$pplex~ty of the issue addressee. For
example, a guideline might state the scientific basis for
the chosen inference option, Me kinds of evidence that
are typically applicable, circumstances in which accept
tance of exceptional evidence may be appropriate, and
other rationales for choosing a particular inference
option.
Regardless of Me form of a guideline, there are some
parts of risk assessment, particularly those dealing with
the quality of data and the magnitude of uncertainty, that
defy or at least resist generic interpretation. Individ-
ual judgment Is most important in such cases. A guide
line should not be viewed as a formula for producing risk
assessments without the need for such judgment.
/
OCR for page 76
76
Mixing of Scientific Knowledge and Risk Assessment Policy
Gu Sidelines unavoidably embody both science if ic knowledge
and risk assessment policy. In the past, regulatory
agencies typically used a conservative approach in the
development of risk assessment policy, as in the choice
of the most sensitive species, use of the most conserva~
tive dose~response curve, and ache lack of acceptance of
negative epidemiologic data. Industry has been highly
critical of this approach. Some representatives believe
that risk assessment should be solely a scientific func-
tion and should be separated from policy decisions.
Consider, for example, the American Industrial Bealth
Councilts criticism of the IRVING guidelines (ATTIC, 1980):
When the IREG report speaks of the importance of
using conservative methods or assumptions so as
not to underestimate human risk, the report is
mixing regulatory considerations into the so lent
tific function. The scientific determination
should be made separately from the regulatory
determinations. On the basis of the best sczenr
tific estimate of the real risk, the regulatory
agency can then consider costs, benefits and other
elements that enter into a regulatory
determination.
Furthermore, there is a fear that the mixing will go
unrecognized outside the scientific community (AIEC,
1980):
When value judgments are formalized by the selec-
tion, for ~conservative. reasons, of a mathematical
model or an assumption used for extrapolating human
risk, the fact that value judgments have been made
escapes the regulator and the public.
The first criticism appears to miss the crucial fact that
risk assessment must always include policy, as well as
The Important issues are what the risk assess-
~nent policy content is and whether it will be applied
consistently or not. The second criticism Is most appli-
cable to guidelines that permit an agency to represent as
science the conclusions that have been reached in part on
the basis of policy considerations. The argument is less
applicable to guidelines that explicitly distinguish
between scientific knowledge and risk assessment policy
OCR for page 77
77
and direct the assessor to address such distinctions when
reaching conclusions. Furthermore, it is not clear that
risk assessment performed on an ad hoc basis would reduce
the opportunity for unrecognized mixing of science and
policy; indeed, carefully designed guidelines could help
to inhibit such mixing.
Guidelines very different from the kinds described
could be designed to be devoid of Disk assessment policy
choices. They would state the scientifically plausible
inference options for each risk assessment component
without attempting to select or even suggest a preferred
inference option. Bowever, a risk assessment based on
such guidelines (containing all the plausible options for
perhaps 40 components) could result in such a wide range
of risk estimates that the analysis would not be useful
to a regulator or to the public. Furthermore, regulators
could reach conclusions based on the ad hoc exercise of
risk assessment policy decisions.
Misallocation of Agency Resources to Development
and Amendment of Guidelines
Critics contend that the dedication of time and resources
to the process of guideline development and amendment
detracts from an agency's ability to conduct regulatory
activities. For example, OS~A's cancer guidelines
required 3 years of effort before promulgation of the
final rule In January 1980. The full rule~making record
eventually exceeded 250,000 pages. OSEA itself offered
some 45 witnesses who addressed the scientific content
and the policy implications of the proposal, and a much
larger number of witnesses appeared in behalf of other
participants. The final policy consisted of more than
280 Federal Resister pages of preamble and a dozen pages
of regulatory text. Notwithstanding this intensive
effort, the guidelines have yet to be applied, and new
leadership at OSHA is in the process of reevaluating some
provisions of the standard.
The procedures required by the Administrative Proce-
dure Act are so elaborate that development and amendment
of guidelines written as regulations are expected to
demand more intensive effort than guidelines written as
established procedures or recommendations. Regardless of
the legal status given to the guidelines, their stability
over time is susceptible to major changes in policy
stances. However, guidelines that clearly distinguish
OCR for page 78
78
scientific knowledge from risk assessment policy judg-
ments could provide a locus for facilitating changes in
policy orientation. They would define elements of risk
assessment policy that are amenable to change and scienr
tific elements that should not be changed for policy
reasons. When risk assessment is done on an ad hoc
basis, such distinctions may not exist.
Freezing of Science
Critics believe that guidelines would hinder the timely
incorporation of important new scientific evidence during
standard-setting.
The Dow Chemical Company raised Ones
concern about OSEA's cancer guidelines (°SBAr 1980):
The record . . . has now made it clear that there
~ s absolutely no assurance that the latest sc' em
tific evidence in the field will be permitted to
be applied under the proposal to any given
regulation of a specific chemical substance.
OSLO responded to this criticism by incorporate ng three
amendment procedures into its cancer policy: a genera'
review of the guidelines every 3 years by the directors
of the National Cancer Institute, the National Institute
of Environmental Health Sciences, and the National Instz-
tute for Occupational Safety and Bealth; recommendations
at any time from the National Cancer Institute, the
National Institute of Environmental Bealth Sciences, or
the National Institute for Occupational Safety and Health;
and petitions from the public. Final amendments would
occur only through formal, independent rule making, to
ensure that major changes in the guidelines would not be
made during the litigation of individual cases. In incus
try's perception, ache amendment provision did not answer
its initial criticism. The A3aeric~" Industrial Bealth
Council characterized the amendment procedures as "a
t~me-consuming and ponderous mechanism for incorporating
into the regulatory standards newly available evidence or
data concerning heretofore unresolved issues" (Osaka,
1980).
This argument is most applicable to guidelines that
are adopted as regulations and to those which are compre-
hensive and inflexible. When guidelines are flexible and
adopted as established procedures or recommendations, the
rapid incorporation of novel scientific information is
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79
more easily accommodated. The intent of flexibility is
to allow the acceptance of exceptional evidence based on
convincing scientif tic justif ication.
In the case of
established procedures or recommendations, changes in
guidelines coul d occur without the necessity of a lengthy
rule~making process.
CONCLUSIONS
.
On the basis of its review of the historical record of
guideline development and use and its evaluation of the
arguments for and against guideline use, the Committee
has drawn several conclusions.
1. All agencies have found it necessary to write
guidelines, in part, to make their choice of inference
options more evident to the public. However, the apuli-
cation of inference options to specific risk assessments
has been marked by a general lack of explicitness.
Because of the lack of explicitness in identifying the
choice of inference options in specific risk assessments,
it has often been difficult to know whether assessors
adhere to guidelines. Within a given program, a consis-
tent set of selected inference options may emerge over
t ~e. However, the degree of consistency Tong programs
and agencies is not well defined.
2. Agency Guidelines have varied markedly in form and
content. Without a deliberate coordinating effort, there
is no reason to assume that Guidelines will became more
nearly uniform.
Although the scientific bases or cancer guidelines
developed in the past by the agencies have been generally
consistent, the degree to which the guidelines are compre-
hensive, detailed, flexible, and legally binding has
varied widely. EPA's guidelines are statements of broad
principles covering a few components in the four steps of
risk assessment; they have no regulatory status. OSEA's
guidelines were comprehensive and detailed and dealt
mainly with hazard identification; they were regulations.
CPSC's guidelines were not comprehensive and dealt mainly
with hazard identification; they had no regulatory status.
FDA's proposed sensitivity~of-method guidelines are cow
prehensive and detailed for dose-response assessment and
exposure assessment; they are regulations. The formation
of the IRLG caused the agencies to adopt a single set of
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80
guidelines for the first tome, but, since its disbanding
in 1981, there has been no Further progress on guideline
development.*
3 Uniform Sidelines for risk assessment (except for
~ ~ ~ ,
exposure assessment) are Feasible and desir ~ le.
Guidelines are feasible. The Committee believes that
current statutory requirements would not prevent the use
of uniform guidelines. Regulators administer laws reflec-
ting social policies that suggest different degrees of
acceptable risk. She argue that uniform guidelines would
keep regulators from applying different standards of risk
that were based on these laws. Bowever, regulators can
apply such standards on the basis of risk management
decisions after completion of the risk assessment. Fur-
thermore, feasibility has already been demonstrated by
the adoption of the IRLG guidelines.
Uniform guidelines are desirable for several reasons.
First, the use of different guidelines by the agencies
could undermine the credibility of their risk assessments.
Critics of an agency risk assessment might argue persuar
sively that another agency estimates risk differently, on
the basis of a different set of inference options.
Second, almost every regulated chemical is in the juris-
dict~on of two or more agencies, and the possibility of
duplication of effort in performing risk asses-~ents on a
given chemical could be minimized if the guidelines were
applied uniformly. Adoption of uniform guidelines could
foster joint risk assessment elms my "y=~- ^..~_
ested in regulating the same chemical; or one agency could
rely on the assessment of another agency. Through such
cooperative efforts, a small agency like CPSC:, which
lacks the scientific capability~of EPA and F=, could
gain help in evaluating complex data. Third, government-
wide guidelines could help industry to gauge government
actions asked to define the types of data and interpreta~
tions relevant to industries' own testing program.
Fourth, federal policy could orchestrate efforts toward
uniformity among the states.
a_ w~ ~__; ~- ~for
_
*The Office of Science and Technology Policy (OSTP), with
agency participation, has written a document describing
the scientific basis of risk assessment. OSTP envisions
the ultimate evolution of a set of principles for risk
assessment from this document.
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81
E - osure guidelines, in contrast with guidelines for
other risk assessment steps, are not now readily amenable
to uniform application in the various agencies. Apart
from EPA, the agencies have rather narrowly defined
interests regarding exposure, i.e., foods and drugs at
FOA, consumer products at CPSC, and occupational hazards
at OSEA. Whereas guidelines for the identification of
hazard and for the quantitative estimation of risk in
test animals may be commonly applied, no such con
basis exists for applying exposure assessment guidelines.
4 Even well-desi~ned guidelines mav be unsuccessful
unless:
.
.
Attention is Liven to the process by which
they are developed.
Thev can accommodate change.
· They are viewed as valuable
f Nebulas for Producing risk assessments.
Because guidelines must include both scientific knowl-
edge and policy judgments, designing a development pro-
cedure is a cliff icult task. Risk assessment requires
advanced knowledge in a number of disciplines, and guide-
l~nes should be formulated in part on the basis of the
best possible scientific expertness in those disciplines.
The best mechanism for determining risk assessment policy
must be carefully defined. Because of the necessity of
considering policy aspects in guidelines, duly appointed
public officials must take responsibility for the policy
implications. A major goal of the development process
should be the assurance that the guidelines preserve a
sharp distinction between scientific knowledge and risk
assessment policy.
The Committee believes that guidelines should be
capable of accommodating evolving scientific concepts in
two ways. First, they should be periodically reviewed
and, if necessary, revised. Second, they should permit
acceptance of new evidence that differs from what was
previously perceived as the general case, when scientifi-
cally justifiable. Bowever, an unavoidable trade-off
results from the use of such flexible guidelines:
predictability and consistency may be reduced for the
sake of flexibility.
Every risk assessment involves consideration of case
specific factors, such as the quality of the data or the
overall strength of the evidence. These factors cannot
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82
be addressed effectively in guidelines. If assessors
were to use guidelines in a strictly mechanical fashion,
without recognizing the importance of case-specific
judgments, the quality of risk assessments could be
diminished.
5. Uniform Guidelines for effects other than cancer
are desirable, but typically they would be based on a
less extensive scientific data base.
The same reasons enunciated for the desirability of
cancer guidelines Impel the conclusion that guidelines
are needed to guide assessments of other effects. Scienr
tific data available on these effects may be organized to
provide useful information for assessing case.
_ _ _1 In facts
guidelines have already been developed for some of these
(although never adopted by the agencies), i.e., guidelines
for mutagenesis (EPA, 1980; March of Dimes Birth Defects
Foundation, 1983~) and guidelines for reproductive and
teratogen~c effects tORNL/EPA, 1982 ; March of Domes Birth
Defects Foundation, 1981).
~E=NCES
AIEC (American Industrial Bealth Council). October 11,
1979. ALEC comments on: A Report of the Interagency
Regulatory Liaison Group (IRKING), Work Group on Risk
Assessment, entitled Unscientific Basis for Identificar
tion of Potential Carcinogens and Estimation of
Risks,. p. 2.
AIEC (American Industrial Bealth Council). April 3G,
1980. In Review of Public Comments on Statement on
Regulation of Chemical Carcinogens; prepared for the
O.S. Regulatory Council, Washington, D.C., pp. B-7,
B-10.
CPSC {Cons'` - er Product Safety Commission). 1978. Interim
policy and procedure for classifying, evaluating, and
regulating carcinogens in consumer products. Fed.
Reg. 43:25658.
EPA (Environmental Protection Agency).
~ . · ~ _..__:, ~
April 5, 1972.
a- =-: ^= ; _ =~- of annex findings J
conclusions and order at 63-64, in re: Stevens Indus.,
Inc. (consolidated DOT hearings).
EPA (environmental Protection Agency). September 5,
1975. Respondents motion to determine whether or not
the registrations of mirex should be canceled or
amended; Attachment A.
Rex ends =~ ^~e ~ && -Ye~ ~=-
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83
EPA (Environmental Protection Agency). 1976. Health
risk and economic impact assessments of suspected
carcinogens. Fed. Reg. 41:21402.
EPA (Environmental Protection Agency). 1980a. Mutagen-
ic~ty risk assessments; proposed guidelines. Fed.
Reg. 45:74984.
EPA Environmental Protection Agency).
Office of Water
Regulations and Standards. 1980b. Water quality
criteria documents; availability. Fed. Reg.
45: 79350-79353 .
EPA (Environmental Protection Agency). Office of
Research and Development, Carcinogen Assessment
Group. August 8, 1980c. The Carcinogen Assessment
Group's method for determining the unit risk estimate
for air pollutants. External review copy, prepared
for Office of Air Quality Planning and Standards and
Office of Air, Noise and Radiation.
FDA (Food and Drug Administration). 1973. Chemical
compounds in food-producing animals; criteria and
procedures for evaluating assays for carcinogenic
residues. Fed. Reg. 38:19226.
FDA tFood and Drug Administration) . 1977 . Ch^mica 1
compounds in food-producing animals; criteria and
procedures for evaluating assays for carcinogenic
residues. Fed. Reg. 42:10412.
FDA (Food and Drug Administration). 1979a. Assessment
of Estimated Risk Resulting from Aflatoxins in
Consumer Product Peanut Products and Other Contami-
nants. Rock~ille, Md.: Food and Drug Administration.
FDA (Food and Drug Administration). 1979b. Chemical
compounds in fo~producing animals; criteria and
procedures for evaluating assays for carcinogenic
residues. Fed. Reg. 44:17070.
FDA (Food and Drug Administration) . }982a. Code o
Federal Regulations, Title 21, Section 10.90.
Washington, D.C.: O.S. Goverrment Printing Office.
FOA (Food and Drug Administration). }982b. D & C Green,
No. 6, listing as a color additive in externally
applied drugs and cosmetics. Fed. Reg. 47:14138.
IRAC (International Agency for Research on Cancer). 1982.
General principles for evaluating the carcinogenic
risk of chemicals; in IAMB monographs on We
Evaluation of the Carcinogenic Risk of Chemicals to
Pans. IARC, Lyon, France, vol. 29.
I=G (Interagency Regulatory Liaison Group), work Group
on Risk Assessment. 1979a. Scientific bases for
identification of potential carcinogens and estimation
of risks. Fed. Reg . 44:39858.
OCR for page 84
84
IRI'G (Interagency Regulatory Liaison Group), Work Group
on Risk Assessment. 19795. Scientific bases for
identification of potential carcinogens and estimation
of risks. J. Natl. Cancer Inst. 63: 242.
Joint Food and Agricultural Organization and World Health
Organization Expert Committee on Pesticide Residues.
1965. Evaluati on of the Toxicity of Pesticide
Residues in Food: Report of the 2nd Joint Meeting.
FAO Meet. Rep. No. PL/1965/10, t~IO/Food Add./26.65.
Joint Food and Agricultural Organization and world Health
Organization Expert Committee on Food Additives.
1972. Evaluation of Certain Food Additives and the
Contaminants Mercury, Lead, and Cadmium. WHO Tech.
Rep. Ser. SQ5. Geneva.
Lehman, A. J., F. A. Vorhes, fir., L. L. Ramsey, E. C.
Hagan, O. G. Fitzhugh, P. J. Schouboe, J. H. Draize,
E . I . Goldenthal, W. ~ 'Aguanr~o, E. T. Lang, E . J.
Omberger, J. B. Gass, R. E. Zwickey, E. J. Davis, ~ .
A. Braun, A. A. Nelson, and B. 3. Vos. 1959.
Appraisal of the Safety of Chemicals in Foods, Drugs
and Cosmetics. Association Food and Drug Officials of
the United States (AFOOUS).
March of Dies Birth Defects Foundation.
January 26-27,
1981. Guidelines for Studies of Bran Populations
Exposed to Mutagenic and Reproductive Hazards;
Proceedings of Conference, Washington, O.C.
PK:/NAS (National Research CounciV~at~ona1 Academy of
Sciences), Food Protection Committee, Food and
Nutrition Board. 1970. Evaluating the Safety of Food
Chemicals. Washington, D.C.: National Academy? of
Sciences.
OR~/EPA (Oak Ridge National Laboratory/Environmental
Protection Agency). February 1982. Assessment of
Risks to Human Reproduction and to Development of Me
Euman Conceptus from Exposure to Environmental
Substances. ORNL/EIS-197, EPA/9-82-001.
.OSEA (Occupational Safety and Health Administration).
1977. Proposed rule: identification, classification
and regulation of potential occupational carcinogens.
Fed. Reg. 42:54148.
O SEA (Occupational Safety and Bealth Administration).
1980. Final rule: identification, classification and
regulation of potential occupat tonal carcinogens.
Fed. Reg. 45:5001.
O SEA (Occupational Safety and Bealth Administration).
1981. Identif ication, class'f icat' on arid regulation
of potential occupational carcinogens; conforming
deletions. Fed. Reg. 46: 4889 .
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OSLO (Occupational Safety and Health A - inistratzon).
1982. Identif ication, classif ication and regulation
of potential occupational carcinogens. Fed. Reg.
47:187.
OSTP (Office of Science and Technology Policy), Regulatory
Work Group on Science and Technology, Executive Office
of the President. October 1, 1982. Potential Bum an
Carcinogens: Methods for Identification and Chateau
terization. Part 1: Current Views: Discussion Draft.
Regulatory Council. 1979. Statement on regulation of
chemical carcinogens: policy and retest for public
comment. Fed. Reg. 44: 60038.
State of California, Bealth and Welfare Agency. July
1982a. Carcinogen Identification Policy: A Statement
of Science as a Basis of Policy.
State of California, Bealth and Welfare Agency. October
1982b. Carcinogen Identification Policy: A Statement
of Science as a Basis of Policy; Section 2: Methods
for Estimating Cancer Risks from Exposures to
Carcinogens.
Representative terms from entire chapter:
assessment policy
